Remedies or prophylactics for diseases in association with chemokines

ABSTRACT

This invention provides remedies or prophylactics for diseases in association with chemokines such as MIP-1 α and/or MCP-1. Namely, remedies or prophylactics for diseases in association with the chemokines such as rheumatoid arthritis or nephritis contain, as the active ingredient, cyclic amine derivatives represented by the following formula (I), pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C 1 -C 6  alkyl addition salts thereof.

BACKGROUND OF THE INVENTION

1. Technical Field

The present invention relates to cyclic amine derivatives and more particularly it relates to chemokine receptor antagonists capable of expecting effects as remedies and/or prophylactics for diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, pulmonary fibrosis, cardiomyopathy, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, sepsis, allergic rhinitis and allergic dermatitis wherein infiltration of blood leukocyte components such as monocytes or lymphocytes into tissues plays a principal role in progression and maintenance of diseases.

2. Background Art

Chemokines are a generic name of a group of inflammatory/immunomodulatory polypeptides having a molecular weight of 6 to 15 KD and produced in inflammatory sites by various kinds of cells, for example, macrophages, monocytes, eosinophils, neutrophils, fibroblasts, vascular endothelial cells, smooth muscle cells and mast cells. The chemokines are classified into two major subgroups of CXC chemokines (or α-chemokines) and CC chemokines (or β-chemokines) by the common location of four preserved cysteine residues and a difference in chromosomal locations of genes encoding the chemokines. The first two cysteines of the CXC chemokines are separated by one amino acid; however, the same cysteines of the CC chemokine are adjacent. For example, IL-8 (an abbreviation for interleukin-8) is the CXC chemokines. On the other hand, MIP-1 α/β (an abbreviation for macrophage inflammatory protein-1 α/β), MCP-1 (an abbreviation for monocyte chemoattractant protein-1) and RANTES (an abbreviation for regulated upon activation, normal T-cell expressed and secreted) are cited as the CC chemokines.

Furthermore, there also exist chemokines which do not fall into either of chemokine subgroups. Lymphotactin having only two cysteines and classified as C chemokines and fractalkine classified as CX3C chemokines because the first two cysteines are separated by three amino acids and having a chemokinelike domain in the mucin structure are cited as such a chemokine. The chemokines promote cell migration and have expression enhancing actions on cellular adhesion molecules such as integrins and further cellular adhesion enhancing actions. Therefore, the chemokines are thought to be protein factors closely involved in the adhesion and infiltration of leukocytes or the like into the pathogenic sites such as inflammatory tissues. See, for example, The Chemokine Facts Book, by Vaddi, K. et al., Academic Press, 1997; Chemoattractant Ligand and Their Receptors, edited by Horuk, R., CRC Press, 1996; Ward, G. W. et al., Biochem. J., 1998, 333, 457; Luster, A. D., New Engl. J. Med., 1998, 338, 436; Bagglioni, M., Nature, 1998, 392, 565; Rolins. B. J., Blood, 1997, 90, 909; Alam, R., J. Allergy Clin. Immunol., 1997, 99, 273; Hancock, W. W., Am. J. Pathol., 1996, 148, 681; Taub, D. D., Cytokine & Growth Factor Rev., 1996, 7, 335; Strieter, R. M. et al., J. Immunol., 1996, 156, 3583; Furie, M. B. et al., Am. J. Pathol., 1995, 146, 1287; Schall, T. J. et al., Current Opinion in Immunology, 1994, 6, 865; and Edginton, S. M., Biotechnology, 1993, 11, 676 as references.

For example, MIP-1 α causes a transient increase in intracellular calcium ion concentration levels and induces cell migration of T lymphocytes or B lymphocytes (see, for example, Tabu, D. D. et al., Science, 1993, 260, 355 and Shall, T. J. et al., J. Exp. Med., 1993, 177, 1821), cell migration of eosinophils (see, for example, Rot, A. et al., J. Exp. Med., 1992, 176, 1489), cell migration of NK cells (see, for example, Magazachi, A. A. et al., J. Immunol., 1994, 153, 4969), expression of integrins (see, for example, Vaddi, K. et al., J. Immunol., 1994, 153, 4721) and differentiation of osteoclasts (see, for example, Kukita, T. et al., Lab. Invest., 1997, 76, 399). MIP-1 α also increases the IgE and IgG4 production in B cells (see, for example, Kimata, H. et al., J. Exp. Med., 1996, 183, 2397) and inhibits the proliferation of hematopoietic stem cells (see, for example, Mayani, H. et al., Exp. Hematol., 1995, 23, 422; Keller, J. R. et al., Blood, 1994, 84, 2175; Eaves, C. J. et al., Proc. Natl. Acad. Sci. USA, 1993, 90, 12015; Bodine, D. M. et al., Blood, 1991, 78, 914; and Broxmeyer, H. E. et al., Blood, 1990, 76, 1110).

As to the association of MIP-1 α with in vivo actions or pathogenesis of diseases, it has been reported that the MIP-1 α is a pyrogen in rabbits (see, for example, Davatelis, G. et al., Science, 1989, 243, 1066) and the injection of the MIP-1 α into the footpads of mice results in inflammatory reactions such as infiltration of neutrophils or mononuclear cells (see, for example, Alam, R. et al., J. Immunol., 1994, 152, 1298).

It has been also reported that a neutralizing antibody to MIP-1 α has inhibitory effects or remedial effects in animal models of granuloma (see, for example, Lukacs, N. W. et al., J. Exp. Med., 1993, 177, 1551), asthma (see, for example, Lukacs, N. W. et al., Eur. J. Immunol., 1995, 25, 245 and Lukacs, N. W. et al., J. Immunol., 1997, 158, 4398), multiple sclerosis (see, for example, Karpus, W. J. et al., J. Immunol., 1995, 155, 5003 and Karpus, W. J. et al., J. Leukoc. Biol., 1997, 62, 681), idiopathic pulmonary fibrosis (see, for example, Smith, R. E. et al., J. Immunol., 1994, 153, 4704 and Smith, R. E., Biol. Signals, 1996, 5, 223), acute lung injury (see, for example, Shanley, T. P. et al., J. Immunol., 1995, 154, 4793 and Standiford, T. J. et al., J. Immunol., 1995, 155, 1515) and rheumatoid arthritis (see, for example, Kasama, T. et al., J. Clin. Invest., 1995, 95, 2868) and the like. Furthermore, it has been reported that coxsackie virus infection-induced myocarditis or herpes stromal keratitis is inhibited in MIP-1α gene deficient mice (see, for example, Cook, D. N. et al., Science, 1995, 269, 1583 and Tumpey, T. M. et al., J. Virology, 1998, 72, 3705).

In addition, significant expression of MIP-1 α was recognized in patients such as chronic pulmonary inflammatory diseases (see, for example, Standiford, T. J. et al., J. Immunol., 1993, 151, 2852), hypersensitivity pneumonitis (see, for example, Denis, M., Am. J. Respir. Crit. Care Med., 1995, 151, 164), rheumatoid arthritis (see, for example, Koch, A. E. et al., J. Clin. Invest., 1994, 93, 921), infectious meningitis (see, for example, Lahrtz, F. et al., J. Neuroimmunol., 1998, 85, 33) and chronic inflammation of muscle (see, for example, Adams, E. M. et al., Proc. Assoc. Am. Physicians, 1997, 109, 275). The studies indicate that MIP-1 α is deeply involved in the local accumulation of various subtypes of leukocytes in association with initiation, progression and maintenance of inflammatory diseases.

MCP-1 [also known as MCAF (an abbreviation for macrophage chemotactic and activating factor) or JE] is a CC chemokine produced by monocytes/macrophages, smooth muscle cells, fibroblasts and vascular endothelial cells and has a cell migration activity and cell adhesion enhancing actions on monocytes (see, for example, Valente, A. J. et al., Biochemistry, 1988, 27, 4162; Matsushima, K. et al., J. Exp. Med., 1989, 169, 1485; Yoshimura, T. et al., J. Immunol., 1989, 142, 1956; Rollins, B. J. et al., Proc. Natl. Acad. Sci. USA, 1988, 85, 3738; Rollins, B. J. et al., Blood, 1991, 78, 1112; Jiang, Y. et al., J. Immunol., 1992, 148, 2423; and Vaddi, K. et al., J. Immunol., 1994, 153, 4721), memory T lymphocytes (see, for example, Carr., M. W. et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 3652), T lymphocytes (see, for example, Loetscher, P. et al., FASEB J., 1994, 8, 1055) and natural killer cells (NK cells) (see, for example, Loetscher, P. et al., J. Immunol., 1996, 156, 322 and Allavena, P. et al., Eur. J. Immunol., 1994, 24, 3233) or the like and MCP-1 further has actions as a histamine releasing factor from basophils (see, for example, Alam R. et al., J. Clin. Invest., 1992, 89, 723; Bischoff, S. C. et al., J. Exp. Med., 1992, 175, 1271; and Kuna, P. et al., J. Exp. Med., 1992, 175, 489).

Moreover, remarkable expression of MCP-1 has been reported in diseases in which the accumulation of monocytes/macrophages and/or T cells is thought to be deeply involved in initiation, progression and maintenance of lesions such as atherosclerosis (see, for example, Hayes, I. M. et al., Arterioscler. Thromb, Vasc. Biol., 1998, 18, 397; Takeya, M. et al., Hum. Pathol., 1993, 24, 534; Yla-Herttuala, S. et al., Proc. Natl. Acad. Sci. USA, 1991, 88, 5252; and Nelken, N. A., J. Clin. Invest., 1991, 88, 1121), rheumatoid arthritis (see, for example, Koch, A. E. et al., J. Clin. Invest., 1992, 90, 772; Akahoshi, T. et al., Arthritis Rheum., 1993. 36, 762; and Robinson, E. et al., Clin. Exp. Immunol., 101, 398), nephritis (see, for example, Noris, M. et al., Lab. Invest., 1995, 73, 804; Wada, T. et al., Kidney Int., 1996, 49, 761; and Gesualdo, L. et al., Kidney Int., 1997, 51, 155), nephropathy (see, for example, Saitoh, A. et al., J. Clin. Lab. Anal., 1998, 12, 1; Yokoyama, H. et al., J. Leukoc. Biol., 1998, 63, 493), pulmonary fibrosis and pulmonary sarcoidosis (see, for example, Sugiyama, Y. et al., Internal Medicine, 1997, 36, 856), asthma (see, for example, Karina, M. et al., J. Invest. Allergol. Clin. Immunol., 1997, 7, 254; Stephene, T. H., Am. J. Respir. Crit. Care Med., 1997, 156, 1377; and Sousa, A. R. et al., Am. J. Respir. Cell Mol. Biol., 1994, 10, 142), multiple sclerosis (see, for example, McManus, C. et al., J. Neuroimmunol., 1998, 86, 20), psoriasis (see, for example, Gillitzer, R. et al., J. Invest. Dermatol., 1993. 101, 127), inflammatory bowel disease (see, for example, Grimm, M. C. et al., J. Leukoc. Biol., 1996, 59, 804 and Reinecker, H. C. et al., Gastroenterology, 1995, 106, 40), cardiomyopathy (see, for example, Seino, Y. et al., Cytokine, 1995, 7, 301), endometriosis (see, for example, Jolicoeur, C. et al., Am. J. Pathol., 1998, 152, 125), intraperitoneal adhesion (see, for example, Zeyneloglu, H. B. et al., Human Reproduction, 1998, 13, 1194), congestive heart failure (see, for example, Aurust, P. et al., Circulation, 1998, 97, 1136), chronic liver disease (see, for example, Marra, F. et al., Am. J. Pathol., 1998, 152, 423), viral meningitis (see, for example, Lahrtz, F. et al., Eur. J. Immunol., 1997, 27, 2484), Kawasaki disease (see, for example, Wong, M. et al., J. Rheumatol., 1997, 24, 1179) and sepsis (see, for example, Salkowski, C. A. et al., Infect. Immun., 1998, 66, 3569).

The inhibitory effects or remedial effects of an anti-MCP-1 antibody have been reported in animal models such as rheumatoid arthritis (see, for example, Schimmer, R. C. et al., J. Immunol., 1998, 160, 1466; Schrier, D. J., J. Leukoc. Biol., 1998, 63, 359; and Ogata H. et al., J. Pathol., 1997, 182, 106), multiple sclerosis (see, for example, Karpus, W. J., J. Leukoc. Biol., 1997, 62., 681), nephritis (see, for example, Lloyd, C. M. et al., J. Exp. Med., 1997, 185, 1371 and Wada T. et al., FASEB J., 1996, 10, 1418), asthma (see, for example, Gonzalo, J.-A. et al., J. Exp. Med., 1998, 188, 157 and Lukacs, N. W., J. Immunol., 1997, 158, 4398), atherosclerosis (see, for example, Guzman, L. A. et al., Circulation, 1993, 88 (suppl.), I-371), delayed type hypersensitivity (see, for example, Rand, M. L. et al., Am. J. Pathol., 1996, 148, 855), pulmonary hypertension (see, for example, Kimura, H. et al., Lab. Invest., 1998, 78, 571) and intraperitoneal adhesion (see, for example, Zeyneloglu, H. B. et al., Am. J. Obstet. Gynecol., 1998, 179, 438).

Further, it has been reported that MCP-1 (9-76) which is a peptide antagonist of MCP-1 inhibits arthritis in the mouse model (see, for example, Gong, J.-H., J. Exp. Med., 1997, 186, 131) and that MCP-1 is essential to monocyte mobilization in vivo in studies on MCP-1 gene deficient mice (see, for example, Lu, B. et al., J. Exp. Med., 1998, 187, 601 and Gu, L. et 41., Moll. Cell, 1998, 2, 275).

These data indicate that chemokines such as MIP-1 α and MCP-1 accumulate monocytes, lymphocytes or the like in disease sites and activate the cells and thus strongly suggest that the chemokines are deeply associated with initiation, progression and maintenance of diseases wherein monocytes, lymphocytes and the like are assumed to be deeply associated with the progression of lesion, for example, atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, pulmonary fibrosis, myocarditis, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease and sepsis (see, for example, Rovin, B. H. et al., Am. J. Kidney. Dis., 1998, 31, 1065; Lloyd, C. et al., Curr. Opin. Nephrol. Hypertens., 1998, 7, 281; Conti, P. et al., Allergy and Asthma Proc., 1998, 19, 121; Ransohoff, R. M. et al., Trends Neuroscience., 1998, 21, 154; and MacDermott, R. P. et al., Inflammatory Bowel Diseases, 1998, 4, 54). A drug which inhibits actions of chemokines on target cells, therefore, can be expected to be useful as remedies and/or prophylactics for the diseases.

On the other hand, the cloning of genes encoding specific receptors for chemokines has been promoted, and it has become apparent that the receptors are G protein-coupled seven-transmembrane receptors present on various leukocytes. At least 5 CXC chemokine receptors (CXCR1 to CXCR5) and eight CC chemokine receptors (CCR1 to CCR8) have hitherto'been specified. For example, IL-8 is a ligand of CXCR1 and CXCR2. MIP-1 α is a ligand of CCR1 and CCR5, and MCP-1 is a ligand of CCR2A and CCR2B (see, for example, Holmes, W. E. et al., Science, 1991, 253, 1278-1280; Murphy, P. M. et al., Science, 253, 1280-1283; Neote, K. et al., Cell, 1993, 72, 415-425; Charo, I. F. et al., Proc. Natl. Acad. Sci., USA, 1994, 91, 2752-2756; Yamagami, S. et al., Biochem. Biophys. Res. Commun., 1994, 202, 1156-1162; Combadier, C. et al., The Journal of Biological Chemistry, 1995, 270, 16491-16494; Power, C. A. et al., J. Biol. Chem., 1995, 270, 19495-19500; Samson, M. et al., Biohemistry, 1996, 35, 3362-3367; and Murphy, P. M. et al., Annual Review of Immunology, 1994, 12, 592-633).

Further, it has been reported that the pulmonary inflammation and granuloma are suppressed in CCR1 gene deficient mice (see, for example, Gao, J.-L. et al., J. Exp. Med., 1997, 185, 1959 and Gerard, C. et al., J. Clin. Invest., 1997, 100, 2022) and that accumulation of macrophages and formation of atherosclerotic lesions are decreased in CCR2 gene deficient mice (see, for example, Boring, L. et al., Nature, 1998, 394, 894; Kuziel, W. A. et al., Proc. Natl. Acad. Sci. USA, 1997, 94, 12053; Kurihara, T. et al., J. Exp. Med., 1997, 186, 1757; and Boring, L. et al., J. Clin. Invest., 1997, 100, 2552). Therefore, compounds capable of inhibiting binding of chemokines such as MIP-1 α and/or MCP-1 to the receptors, i.e. chemokine receptor antagonists can be expected to be useful as a drug which inhibits the actions of the chemokines such as MIP-1 α and/or MCP-1 on target cells; however, the drug having the actions is not known.

Cyclic amine derivatives such as various kinds of piperidines or piperazines have recently been reported to have chemokine receptor antagonistic activity (see, for example, WO9724325; Hesselgesser, J. et al., J. Biol. Chem., 1998, 273, 15687; Howard, O. M. Z. et al., J. Med. Chem., 1998, 41, 2184; WO9744329; WO9802151; WO9804554; WO9825605; WO9825617; WO9825604; WO9831364; WO9856771; WO9909984; WO9904794; WO9917773; WO9937617; WO9937619; WO9737651; WO9938514; WO200014086; WO200014089; EP903349; JP9-249566; JP9-25572; and JP11-711350). The compounds, however, are different from the compounds used in the present invention.

BRIEF SUMMARY OF THE INVENTION

It is an object of the present invention to provide therapies for diseases wherein the binding of chemokines such as MIP-1 α and/or MCP-1 to receptors on target cells is one of the pathogenesis by using a small-molecular compound having an inhibitory activity against the binding of the chemokines such as MIP-1 α and/or MCP-1 to the receptors on the target cells.

As a result of intensive studies, the present inventors have found that cyclic amine derivatives having an arylalkyl group, pharmaceutically acceptable C₁-C₆ alkyl-addition salts thereof or pharmaceutically acceptable acid-addition salts thereof have an inhibitory activity against the binding of chemokines such as MIP-1 α and/or MCP-1 to the target cells and that the compounds can be useful as remedies or prophylactics for diseases considered to be associated with the chemokines such as MIP-1 α and/or MCP-1. The present invention has been accomplished on the basis of the findings.

That is, the present invention is remedies or prophylactics for diseases in association with chemokines or chemokine receptors comprising compounds represented by the following formula (I), pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C₁-C₆ alkyl addition salts thereof as an active ingredient,

wherein R¹ is a phenyl group, a C₃-C₈ cycloalkyl group or an aromatic heterocyclic group having 1- to 3 oxygen atoms, sulfur atoms and/or nitrogen atoms as heteroatoms; the phenyl group or the aromatic heterocyclic group in the R¹ may be condensed with a benzene ring or an aromatic heterocyclic group having 1 to 3 oxygen atoms, sulfur atoms and/or nitrogen atoms as heteroatoms to form a condensed ring; the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring in the above R¹ may be substituted with an optional number of halogen atoms, hydroxy groups, cyano groups, nitro groups, carboxy groups, carbamoyl groups, C₁-C₆ alkyl groups, C₃-C₈ cycloalkyl groups, C₂-C₆ alkenyl groups, C₁-C₆ alkoxy groups, C₁-C₆ alkylthio groups, C₃-C₅ alkylene groups, C₂-C₄ alkylenoxy groups, C₁-C₃ alkylenedioxy groups, phenyl groups, phenoxy groups, phenylthio groups, benzyl groups, benzyloxy groups, benzoylamino groups, C₂-C₇ alkanoyl groups, C₂-C₇ alkoxycarbonyl groups, C₂-C₇ alkanoyloxy groups, C₂-C₇ alkanoylamino groups, C₂-C₇ N-alkylcarbamoyl groups, C₄-C₈ N-cycloalkylcarbamoyl groups, C₁-C₆ alkylsulfonyl groups, C₃-C₈ (alkoxycarbonyl)methyl groups, N-phenylcarbamoyl groups, piperidinocarbonyl groups, morpholinocarbonyl groups, 1-pyrrolidinylcarbonyl groups, bivalent groups represented by the formula; —NH(C═O)O—, bivalent groups represented by the formula: —NH(C═S)O—, amino groups, mono(C₁-C₆ alkyl)amino groups or di(C₁-C₆ alkyl)amino groups; the substitutent groups of the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring may further be substituted with an optional number of halogen atoms, hydroxy groups, amino groups, trifluoromethyl groups, C₁-C₆ alkyl groups or C₁-C₆ alkoxy groups,

R² is a hydrogen atom, a C₁-C₆ alkyl group, a C₂-C₇ alkoxycarbonyl group, hydroxy group or a phenyl group; the C₁-C₆ alkyl group or the phenyl group in the R² may be substituted with an optional number of halogen atoms, hydroxy groups, C₁-C₆ alkyl groups or C₁-C₆ alkoxy groups, with the proviso that R² is not hydroxy group when j is 0;

j is an integer of 0 to 2;

k is an integer of 0 to 2;

m is an integer of 2 to 4;

n is 0 or 1;

R³ is a hydrogen atom or a C₁-C₆ alkyl group which may be substituted with (one or two phenyl groups which may respectively be substituted with an optional number of the same or different halogen atoms, hydroxy groups, C₁-C₆ alkyl groups or C₁-C₆ alkoxy groups);

R⁴ and R⁵ are the same or different and are each a hydrogen atom, a hydroxy group, a phenyl group or a C₁-C₆ alkyl group; the C₁-C₆ alkyl group in the R⁴ and R⁵ may be substituted with an optional number of halogen atoms, hydroxy groups, cyano groups, nitro groups, carboxy groups, carbamoyl groups, mercapto groups, guanidino groups, C₃-C₈ cycloalkyl groups, C₁-C₆ alkoxy groups, C₁-C₆ alkylthio groups, (phenyl groups which may be substituted with an optional number of halogen atoms, hydroxy groups, C₁-C₆ alkyl groups, C₁-C₆ alkoxy groups or benzyloxy groups), phenoxy groups, benzyloxy groups, benzyloxycarbonyl groups, C₂-C₇ alkanoyl groups, C₂-C₇ alkoxycarbonyl groups, C₂-C₇ alkanoyloxy groups, C₂-C₇ alkanoylamino groups, C₂-C₇ N-alkylcarbamoyl groups, C₁-C₆ alkylsulfonyl groups, amino groups, mono(C₁-C₆ alkyl)amino groups, di(C₁-C₆ alkyl)amino groups or (aromatic heterocyclic groups having 1 to 3 oxygen atoms, sulfur atoms and/or nitrogen atoms as heteroatoms or condensed rings formed by condensation of the aromatic heterocyclic groups having the 1 to 3 oxygen atoms, sulfur atoms and/or nitrogen atoms as the heteroatoms with benzene rings) or both R⁴ and R⁵ together may form a 3- to a 6-membered cyclic hydrocarbon;

p is 0 or 1;

q is 0 or 1;

G is a group represented by —CO—, —SO₂—, —CO—O—, —NR⁷—CO—, CO—NR⁷—, —NH—CO—NH—, —NH—CS—NH—, —NR⁷—SO₂—, —SO₂—NR⁷—, —NH—CO—O— or —O—CO—NH—,

wherein R⁷ is a hydrogen atom or a C₁-C₆ alkyl group or R⁷, together with R⁵, may form a C₂-C₅ alkylene group;

R⁶ is a phenyl group, a C₃-C₈ cycloalkyl group, a C₃-C₆ cycloalkenyl group, a benzyl group or an aromatic heterocyclic group having 1 to 3 oxygen atoms, sulfur atoms and/or nitrogen atoms as heteroatoms; the phenyl group, the benzyl group or the aromatic heterocyclic group in the R⁶ may be condensed with a benzene ring or an aromatic heterocyclic group having 1 to 3 oxygen atoms, sulfur atoms and/or nitrogen atoms as heteroatoms to form a condensed ring; the phenyl group, the C₃-C₈ cycloalkyl group, the C₃-C₆ cycloalkenyl group, the benzyl group, the aromatic heterocyclic group or the condensed ring in the above R⁶ may further be substituted with an optional number of halogen atoms, hydroxy groups, mercapto groups, cyano groups, nitro groups, thiocyanato groups, carboxy groups, carbamoyl groups, trifluoromethyl groups, C₁-C₆ alkyl groups, C₃-C₈ cycloalkyl groups, C₂-C₆ alkenyl groups, C₁-C₆ alkoxyl groups, C₃-C₈ cycloalkyloxy groups, C₁-C₆ alkylthio groups, C₁-C₃ alkylenedioxy groups, phenyl groups, phenoxy groups, phenylamino groups, benzyl groups, benzoyl groups, phenylsulfinyl groups, phenylsulfonyl groups, 3-phenylureido groups, C₂-C₇ alkanoyl groups, C₂-C₇ alkoxycarbonyl groups, C₂-C₇ alkanoyloxy groups, C₂-C₇ alkanoylamino groups, C₂-C₇ N-alkylcarbamoyl groups, C₁-C₆ alkylsulfonyl groups, phenylcarbamoyl groups, N,N-di(C₁-C₆ alkyl)sulfamoyl groups, amino groups, mono(C₁-C₆ alkyl)amino groups, di(C₁-C₆ alkyl)amino groups, benzylamino groups, C₂-C₇ (alkoxycarbonyl)amino groups, C₁-C₆ (alkylsulfonyl)amino groups or bis(C₁-C₆ alkylsulfonyl)amino groups; the substitutent groups of the phenyl group, the C₃-C₈ cycloalkyl group, the C₃-C₈ cycloalkenyl group, the benzyl group, the aromatic heterocyclic group or the condensed ring may further be substituted with an optional number of halogen atoms, cyano groups, hydroxy groups, amino groups, trifluoromethyl groups, C₁-C₆ alkyl groups, C₁-C₆ alkoxyl groups, C₁-C₆ alkylthio groups, mono(C₁-C₆ alkyl)amino groups or di(C₁-C₆ alkyl)amino groups.

The compounds represented by the above formula (I) have an inhibitory activity against the binding of chemokines such as MIP-1 α and/or MCP-1 to target cells and an inhibitory activity against physiological actions of the chemokines such as MIP-1 α and/or MCP-1 on the target cells.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a drawing illustrating effects of Compd. No. 1583 on arthritis when the compound is orally administered for 12 weeks.

FIG. 2 is a drawing illustrating effects of the Compd. No. 1,583 on synovial hyperplasia.

FIG. 3 is a drawing illustrating effects of the Compd. No. 1583 on the chondrolysis of articular cartilages.

FIG. 4 is a drawing illustrating effects of the Compd. No. 1583 on the osteolysis of subchondral bone.

FIG. 5 is a drawing illustrating effects of Compd. No. 1245 on hindlimb footpads swelling when the compound is orally administered for 3 weeks.

FIG. 6 is a drawing illustrating suppressive effects of the Compd. No. 1583 on proteinuria.

FIG. 7 is a drawing illustrating suppressive effects of the Compd. No. 1245 on proteinuria.

FIG. 8 is a drawing illustrating effects of the Compd. No. 1583 in animal models of chronic relapsing experimental allergic encephalomyelitis.

FIG. 9 is a drawing illustrating effects of the Compd. No. 1245 in animal models of chronic relapsing experimental allergic encephalomyelitis.

DETAILED DESCRIPTION OF THE INVENTION

In the above formula (I), R¹ is a phenyl group, a C₃-C₈ cycloalkyl group or an aromatic heterocyclic group having 1 to 3 oxygen atoms, sulfur atoms and/or nitrogen atoms as heteroatoms; the phenyl group or the aromatic heterocyclic group in the above R¹ may be condensed with a benzene ring or an aromatic heterocyclic group having 1 to 3 oxygen atoms, sulfur atoms and/or nitrogen atoms as heteroatoms to form a condensed ring; the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring in the above R¹ may further be substituted with an optional number of halogen atoms, hydroxy groups, cyano groups, nitro groups, carboxy groups, carbamoyl groups, C₁-C₆ alkyl groups, C₃-C₈ cycloalkyl groups, C₂-C₆alkenyl groups, C₁-C₆ alkoxy groups, C₁-C₆ alkylthio groups, C₃-C₅ alkylene groups, C₂-C₄ alkylenoxy groups, C₁-C₃ alkylenedioxy groups, phenyl groups, phenoxy groups, phenylthio groups, benzyl groups, benzyloxy groups, benzoylamino groups, C₂-C₇ alkanoyl groups, C₂-C₇ alkoxycarbonyl groups, C₂-C₇ alkanoyloxy groups, C₂-C₇ alkanoylamino groups, C₂-C₇ N-alkylcarbamoyl groups, C₄-C₈ N-cycloalkylcarbamoyl groups, C₁-C₆ alkylsulfonyl groups, C₃-C₈ (alkoxycarbonyl)methyl groups, N-phenylcarbamoyl groups, piperidinocarbonyl groups, morpholinocarbonyl groups, 1-pyrrolidinyl carbonyl groups, bivalent groups represented by the formula —NH(C═O)O—, bivalent groups represented by the formula —NH(C═S)O—, amino groups, mono(C₁-C₆ alkyl)amino groups or di(C₁-C₆ alkyl)amino groups.

The “C₃-C₈-cycloalkyl group” in R¹ means a cyclic alkyl group, and includes for example cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and the like. The “C₃-C₈ cycloalkyl group” is preferably cyclopropyl group, cyclopentyl group, cyclohexyl group or the like.

The “aromatic heterocyclic group having 1 to 3 oxygen atoms, sulfur atoms and/or nitrogen atoms as heteroatoms” in R¹ means an aromatic heterocyclic group, and includes for example thienyl group, furyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyridyl group, pyrimidinyl group, triazinyl group, triazolyl group, oxadiazolyl (furazanyl) group, thiadiazolyl group and the like. The “aromatic heterocyclic group having 1 to 3 oxygen atoms, sulfur atoms and/or nitrogen atoms as heteroatoms” is preferably thienyl group, furyl group, pyrrolyl group, isoxazolyl group, pyridyl group or the like.

The “condensed ring” in R¹ means a bicyclic aromatic heterocyclic group formed by condensing the phenyl group or the aromatic heterocyclic group with a benzene ring or the aromatic heterocyclic group having 1 to 3 oxygen atoms, sulfur atoms and/or nitrogen atoms as heteroatoms in an optional position, and includes for example naphthyl group, indolyl group, benzofuranyl group, benzothienyl group, quinolyl group, benzimidazolyl group, benzoxazolyl group, benzotriazolyl group, benzoxadiazolyl (benzofurazanyl) group, benzothiadiazolyl group and the like.

Among them, it is especially preferable for R¹ to be a phenyl group, an isoxazolyl group or an indolyl group.

The “halogen atoms” as the substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring mean a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like, and fluorine atom, chlorine atom or bromine atom is specifically preferable.

The “C₁-C₆ alkyl groups” as the substituents of R¹ mean C₁-C₆ straight or branched alkyl groups, and include for example, methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, neopentyl group, tert-pentyl group, isohexyl group, 2-methylpentyl group, 1-ethylbutyl group and the like. The “C₁-C₆ alkyl groups” are specifically preferably methyl group, ethyl group, propyl group, isopropyl group or the like.

The “C₃-C₈ cycloalkyl groups” as the substituents of R¹ are the same as defined in the “C₃-C₈ cycloalkyl group” in the above R¹, and specifically preferably include for example the same groups.

The “C₂-C₆ alkenyl groups” as the substituents of R¹ mean C₂-C₆ straight or branched alkenyl groups, and include for example vinyl group, allyl group, 1-propenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 4-pentenyl group, 5-hexenyl group, 4-methyl-3-pentenyl group and the like. The “C₂-C₆ alkenyl groups” are specifically preferably vinyl group and 2-methyl-1-propenyl group or the like.

The “C₁-C₆ alkoxy groups” as the substituents of R¹ mean groups composed of the above C₁-C₆ alkyl groups and oxy group, and methoxy group, ethoxy group or the like is specifically preferable.

The “C₁-C₆ alkylthio groups” as the substituents of R¹ mean groups composed of the above C₁-C₆ alkyl groups and thio group, and methylthio group, ethylthio group or the like is specifically preferable.

The “C₃-C₅ alkylene groups” as the substituents of R¹ mean C₃-C₅ bivalent alkylene groups, and include for example, trimethylene group, tetramethylene group, pentamethylene group, 1-methyltrimethylene group and the like. The “C₃-C₅ alkylene groups” are specifically preferably trimethylene group, tetramethylene group or the like.

The “C₂-C₄ alkylenoxy groups” as the substituents of R¹ mean groups composed of C₂-C₄ bivalent alkylene groups and oxy group and include, for example, ethylenoxy group (—CH₂CH₂O—), trimethylenoxy group (—CH₂CH₂CH₂O—), tetramethylenoxy group (—CH₂CH₂CH₂CH₂O—), 1,1-dimethylethylenoxy group (—CH₂C(CH₃)₂O—) and the like. The “C₂-C₄ alkylenoxy groups” are specifically preferably ethyleneoxy group, trimethylenoxy group or the like.

The “C₁-C₃ alkylenedioxy groups” as the substituents of R¹ mean groups composed of C₁-C₃ bivalent alkylene groups and two oxy groups and include, for example, methylenedioxy group (—OCH₂O—), ethylenedioxy group OCH₂CH₂O—), trimethylenedioxy (—OCH₂CH₂CH₂O—) group and propylenedioxy (—OCH₂CH(CH₃)O—) group and the like. The “C₁-C₃ alkylenedioxy groups” are specifically preferably methylenedioxy group, ethylenedioxy group or the like.

The “C₂-C₇ alkanoyl groups” as the substituents of R¹ mean C₂-C₇ straight or branched alkanoyl groups, and include for example, acetyl group, propanoyl group, butanoyl group, pentanoyl group, hexanoyl group, heptanoyl group, isobutyryl group, 3- methylbutanoyl group, 2- methylbutanoyl group, pivaloyl group, 4-methylpentanoyl group, 3,3-dimethylbutanoyl group, 5-methylhexanoyl group and the like, and acetyl group or the like is specifically preferable.

The “C₂-C₇ alkoxycarbonyl groups” as the substituents of R¹ mean groups composed of the above C₁-C₆ alkoxy groups and carbonyl group, and methoxycarbonyl group, ethoxycarbonyl group or the like is specifically preferable.

The “C₂-C₇ alkanoyloxy groups” as the substituents of R¹ mean groups composed of the above C₂-C₇ alkanoyl groups and oxy group, and acetyloxy group or the like is specifically preferable.

The “C₂-C₇ alkanoylamino groups” as the substituents of R¹ mean groups composed of the above C₂-C₇ alkanoyl groups and amino group, and acetylamino group or the like is specifically preferable.

The “C₂-C₇ alkylcarbamoyl groups” as the substituents of R¹ mean groups composed of the above C₁-C₆ alkyl groups and carbamoyl group, and N-methylcarbamoyl group, N-ethylcarbamoyl group or the like is specifically preferable.

The “C₄-C₉ N-cycloalkylcarbamoyl groups” as the substituents of R¹ mean the above C₃-C₈ cycloalkyl groups and carbamoyl group, and N-cyclopentylcarbamoyl group, N-cyclohexylcarbamoyl group or the like is preferable.

The “C₁-C₆ alkylsulfonyl groups” as the substituents of R¹ mean groups composed of the above C₁-C₆ alkyl groups and sulfonyl group, and methylsulfonyl group or the like is specifically preferable.

The “C₃-C₈ (alkoxycarbonyl)methyl groups” as the substituents of R¹ mean groups composed of the above C₂-C₇ alkoxycarbonyl groups and methyl group, and (methoxycarbonyl)methyl group, (ethoxycarbonyl)methyl group or the like is specifically preferable.

The “mono(C₁-C₆ alkyl)amino groups” as the substituents of R¹ mean amino groups substituted with the above C₁-C₆ alkyl groups, and methylamino group, ethylamino group or the like is specifically preferable.

The “di(C₁-C₆ alkyl)amino groups” as the substituents of R¹ mean amino groups substituted with the same or different two C₁-C₆ alkyl groups described above, and dimethylamino group, diethylamino group, N-ethyl-N-methylamino group or the like is specifically preferable.

Among those described above, examples of the substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring in R¹ are specifically preferably halogen atoms, hydroxy groups, C₁-C₆ alkyl groups, C₂-C₆ alkenyl groups, C₁-C₆ alkoxy groups, C₁-C₆ alkylthio groups, C₂-C₄ alkylenoxy groups, methylenedioxy groups, N-phenylcarbamoyl groups, amino groups, mono(C₁-C₆ alkyl)amino groups and di(C₁-C₆ alkyl)amino groups.

Moreover, the substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring in R¹ may further be substituted with an optional number of halogen atoms, hydroxy groups, amino groups, trifluoromethyl groups, C₁-C₆ alkyl groups or C₁-C₆ alkoxy groups. The halogen atoms, C₁-C₆ alkyl groups and C₁-C₆ alkoxy groups are the same as defined for the substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring in R¹, and the same groups are specifically preferable.

In the above formula (I), R² is a hydrogen atom, a C₁-C₆ alkyl group, a C₂-C₇ alkoxycarbonyl group, a hydroxy group or a phenyl group; and the C₁-C₆ alkyl group or phenyl group in R² may be substituted with an optional number of halogen atoms, hydroxy groups, C₁-C₆ alkyl groups or C₁-C₆ alkoxy groups, with the proviso that R² is not a hydroxy group when j is 0.

The C₁-C₆ alkyl group and C₂-C₇ alkoxycarbonyl group in R² are each the same as defined for the substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring in R¹, and the same examples are specifically preferable.

The halogen atoms, C₁-C₆ alkyl groups and C₁-C₆ alkoxy groups as the substituents of the C₁-C₆ alkyl group or the phenyl group in R² are the same as defined for the substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring in the above R¹, and the same examples are specifically preferable.

Among them, it is especially preferable for R² to be a hydrogen atom.

In the above formula (I), j is an integer of 0 to 2, and it is especially preferable for j to be 0.

In the above formula (I), k is an integer of 0 to 2; m is an integer of 2 to 4. Among them, it is especially preferable for the compounds to be 2-substituted pyrrolidines wherein k is 0 and m is 3; 3-substituted pyrrolidines when k is 1 and m is 2; 3-substituted piperidines wherein k is 1 and m is 3; 4-substituted piperidines wherein k is 2 and m is 2; or 3-substituted hexahydroazepines wherein k is 1 and m is 4.

In the above formula (I), n is 0 or 1.

In particular, 3-amidopyrrolidines wherein k is 1; m is 2 and n is 0 and 4-(amidomethyl)piperidines wherein k is 2; m is 2 and n is 1 are especially preferable.

In the above formula (I), R³ is a hydrogen atom or a C₁-C₆ alkyl group which may be substituted with (one or two phenyl groups which may respectively be substituted with an optional number of the same or different halogen atoms, hydroxy groups, C₁-C₆ alkyl groups or C₁-C₆ alkoxy groups).

The C₁-C₆ alkyl group in R³ is the same as defined for the substituent group of the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring in the above R¹, and methyl group, ethyl group or propyl group is specifically preferable.

The halogen atoms, C₁-C₆ alkyl groups and C₁-C₆ alkoxy groups as the substituents of the phenyl groups as the substituents of the C₁-C₆ alkyl group in R³ are each the same as defined for substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring in the above R¹, and the same examples are specifically preferable.

Among them, it is especially preferable for R³ to be a hydrogen atom.

In the above formula (I), R⁴ and R⁵ are each the same or different and are each a hydrogen atom, a hydroxy group, a phenyl group or a C₁-C₆ alkyl group; and the C₁-C₆ alkyl group in R⁴ and R⁵ may be substituted with an optional number of halogen atoms, hydroxy groups, cyano groups, nitro groups, carboxy groups, carbamoyl groups, mercapto groups, guanidino groups, C₃-C₈ cycloalkyl groups, C₁-C₆ alkoxy groups, C₁-C₆ alkylthio groups, (phenyl groups which may be subst ituted with an optional number of halogen atoms, hydroxy groups, C₁-C₆ alkyl groups, C₁-C₆ alkoxy groups or benzyloxy groups), phenoxy groups, benzyloxy groups, benzyloxycarbonyl groups, C₂-C₇ alkanoyl groups, C₂-C₇ alkoxycarbonyl groups, C₂-C₇ alkanoyloxy groups, C₂-C₇ alkanoylamino groups, C₂-C₇ N-alkylcarbamoyl groups, C₁-C₆ alkylsulfonyl groups, amino groups, mono(C₁-C₆ alkyl)amino groups, di(C₁-C₆ alkyl)amino groups or (aromatic heterocyclic groups having 1 to 3 oxygen atoms, sulfur atoms and/or nitrogen atoms as heteroatoms or condensed rings formed by condensation thereof with benzene rings) or both R⁴ and R⁵ together may form a 3- to a 6-membered cyclic hydrocarbon.

The C₁-C₆ alkyl group in R⁴ and R⁵ is the same as defined for the substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring in the above R¹, and the same examples are specifically preferable.

The halogen atoms, C₁-C₆ alkoxy groups, C₁-C₆ alkylthio groups, C₂-C₇ alkanoyl groups, C₂-C₇ alkoxycarbonyl groups, C₂-C₇ alkanoyloxy groups, C₂-C₇ alkanoylamino groups, C₂-C₇ N-alkylcarbamoyl groups, C₁-C₆ alkylsulfonyl groups, mono(C₁-C₆ alkyl)amino groups and di(C₁-C₆ alkyl)amino groups as the substituents of the C₁-C₆ alkyl group in R⁴ and R⁵ are the same as defined for the substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring in the above R¹, and the same examples are specifically preferable.

The C₃-C₈ cycloalkyl groups and the aromatic heterocyclic groups having 1 to 3 oxygen atoms, sulfur atoms and/or nitrogen atoms as heteroatoms as the substituents of the C₁-C₆ alkyl group in R⁴ and R⁵ are the same as defined for the above R¹, and the same examples are preferable.

The halogen atoms, C₁-C₆ alkyl groups and C₁-C₆ alkoxy groups as the substituents of the phenyl groups as the substituents of the C₁-C₆ alkyl group in R⁴ and R⁵ are the same as defined for the substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring in the above R¹, and the same examples are specifically preferable.

The “3- to 6-membered cyclic hydrocarbon” composed of R⁴, R⁵ and the adjacent carbon atoms are specifically preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane or the like.

Among them, the hydrogen atom and C₁-C₆ alkyl group are especially preferable for R⁴ and R⁵.

In the above formula (I), p is 0 or 1; and q is 0 or 1. Both p and q are especially preferably 0.

In the above formula (I), G is a group represented by —CO—, —SO₂—, —CO—O—, —NR⁷—CO—, —CO—NR⁷—, —NH—CO—NH—, —NH—CS—NH—, —NR⁷—SO₂—, —SO₂—NR⁷—, —NH—CO—O— or —O—CO—NH—,

wherein R⁷ is a hydrogen atom or a C₁-C₆ alkyl group or R⁷, together with R⁵, may form a C₂-C₅ alkylene group,

wherein, —CO— is a carbonyl group, —SO₂— is a sulfonyl group and —CS— is a thiocarbonyl group. G is especially preferably the group represented by —NR⁷—CO— or —NH—CO—NH—.

The C₁-C₆ alkyl group in R⁷ is the same as defined for the substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring in the above R¹, and the same examples are specifically preferable.

The “C₂-C₅ alkylene group” composed of R⁵ and R⁷ means a C₂-C₅ straight or branched alkylene group, for example, methylene group, ethylene group, propylene group, trimethylene group, tetramethylene group, 1-methyltrimethylene group, pentamethylene group and the like, and ethylene group, trimethylene group, tetramethylene group or the like is specifically preferable.

Among them, it is especially preferable for R⁷ to be a hydrogen atom.

In the above formula (I), R⁶ is a phenyl group, a C₃-C₈ cycloalkyl group, a C₃-C₆ cycloalkenyl group, a benzyl group or an aromatic heterocyclic group having 1 to 3 oxygen atoms, sulfur atoms and/or nitrogen atoms as heteroatoms; and the phenyl group, the benzyl group or the aromatic heterocyclic group in the above R⁶ may be condensed with a benzene ring or the aromatic heterocyclic group having 1 to 3 oxygen atoms, sulfur atoms and/or nitrogen atoms as heteroatoms to form a condensed ring; and the phenyl group, the C₃-C₈ cycloalkyl group, the C₃-C₆ cycloalkenyl group, the benzyl group, the aromatic heterocyclic group or the condensed ring in the above R⁶ may be substituted with an optional number of halogen atoms, hydroxy groups, mercapto groups, cyano groups, nitro groups, thiocyanato groups, carboxy groups, carbamoyl groups, trifluoromethyl groups, C₁-C₆ alkyl groups, C₃-C₈ cycloalkyl groups, C₂-C₆ alkenyl groups, C₁-C₆ alkoxyl groups, C₃-C₈ cycloalkyloxy groups, C₁-C₆ alkylthio groups, C₁-C₃ alkylenedioxy groups, phenyl groups, phenoxy groups, phenylamino groups, benzyl groups, benzoyl groups, phenylsulfinyl groups, phenylsulfonyl groups, 3-phenylureido groups, C₂-C₇ alkanoyl groups, C₂-C₇ alkoxycarbonyl groups, C₂-C₇ alkanoyloxy groups, C₂-C₇ alkanoylamino groups, C₂-C₇ N-alkylcarbamoyl groups, C₁-C₆ alkylsulfonyl groups, phenylcarbamoyl groups, N,N-di(C₁-C₆ alkyl)sulfamoyl groups, amino groups, mono(C₁-C₆ alkyl)amino groups, di(C₁-C₆ alkyl)amino groups, benzylamino groups, C₂-C₇ (alkoxycarbonyl)amino groups, C₁-C₆ (alkylsulfonyl)amino groups or bis(C₁-C₆ alkylsulfonyl)amino groups.

The C₃-C₈ cycloalkyl groups, aromatic heterocyclic groups having oxygen atoms, sulfur atoms and/or nitrogen atoms as heteroatoms, or condensed rings in R⁶ are the same as defined for the above R¹, and the same examples are specifically preferable.

The “C₃-C₈ cycloalkenyl groups” in R⁶ mean cycloalkenyl groups, for example, cyclobutenyl group, cyclopentenyl group, cyclohexenyl group, cycloheptenyl group and cyclooctenyl group, and 1- cyclopentenyl group, 1-cyclohexenyl group or the like is specifically preferable.

Among them, it is especially preferable for R⁶ to be a phenyl group, a furyl group and a theinyl group.

The halogen atoms, C₁-C₆ alkyl groups, C₁-C₆ alkenyl groups, C₁-C₆ alkoxy groups, C₁-C₆ alkylthio groups, C₁-C₃ alkylenedioxy groups, C₂-C₇- alkanoyl groups, C₂-C₇ alkoxycarbonyl groups, C₂-C₇ alkanoyloxy groups, C₂-C₇ alkanoylamino groups, C₂-C₇ N-alkylcarbamoyl groups, C₁-C₆ alkylsulfonyl groups, mono(C₁-C₆ alkyl)amino groups and di(C₁-C₆ alkyl)amino groups as the substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the C₃-C₈ cycloalkenyl group, the benzyl group, the aromatic heterocyclic group or the condensed ring in R⁶ are the same as defined for the substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic group or the condensed ring in the above R¹, and the same examples are specifically preferable.

The C₃-C₈ cycloalkyl groups as the substituents of R⁶ are the same as defined for the C₃-C₈ cycloalkyl groups in the above R¹, and the same examples are specifically preferable.

The “C₃-C₈ cycloalkyloxy groups” as the substituents of R⁶ mean groups composed of the above C₃-C₈ cycloalkyl groups and oxy groups, and cyclopropyloxy group, cyclopentyloxy group, cyclohexyloxy group or the like is specifically preferable.

The “N,N-di(C₁-C₆ alkyl)sulfamoyl groups” as the substituents of R⁶ mean sulfamoyl groups substituted with the same or different two C₁-C₆ alkyl groups described above, and N,N-dimethylsulfamoyl group, N,N-diethylsulfamoyl group, N-ethyl- N-methylsulfamoyl group or the like is specifically preferable.

The “C₂-C₇ (alkoxycarbonyl)amino groups” as the substituents of R⁶ mean groups composed of the above C₂-C₇ alkoxycarbonyl groups and amino groups, and (methoxycarbonyl)amino group, (ethoxycarbonyl)amino group or the like is specifically preferable.

The “C₁-C₆ (alkylsulfonyl)amino groups” as the substituents of R⁶ mean groups composed of the above C₁-C₆ alkylsulfonyl groups and amino groups, and (methylsulfonyl)amino group or the like is specifically preferable.

The “bis(C₁-C₆ alkylsulfonyl)amino groups” as the substituents of R⁶ mean amino groups substituted with the same or different two C₁-C₆ alkylsulfonyl groups described above, and bis(methylsulfonyl)amino group or the like is specifically preferable.

Among them, halogen atoms, mercapto groups, nitro groups, thiocyanate groups, trifluoromethyl groups, C₁-C₆ alkyl groups, C₁-C₆ alkoxy groups, phenyl groups, phenylsulfonyl groups, C₂-C₇ alkanoylamino groups, amino groups and the like are especially preferable for the substituents of the phenyl groups, the C₃-C₈ cycloalkyl group, the C₃-C₈ cycloalkenyl group, the benzyl group, the aromatic heterocyclic group or the condensed group in R⁶.

The substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the C₃-C₈ cycloalkenyl group, the benzyl group, the aromatic heterocyclic group or the condensed ring in such R⁶ may further be substituted with an optional number of halogen atoms, cyano groups, hydroxy groups, amino groups, trifluormethyl groups, C₁-C₆ alkyl groups, C₁-C₆ alkoxy groups, C₁-C₆ alkylthio groups, mono(C₁-C₆ alkyl)amino groups or di(C₁-C₆ alkyl)amino groups.

The halogen atoms, C₁-C₆ alkyl groups, C₁-C₆ alkoxy groups, C₁-C₆ alkylthio groups, mono(C₁-C₆ alkyl)amino groups and di(C₁-C₆ alkyl)amino groups as the substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the C₃-C₈ cycloalkenyl group, the benzyl group, the aromatic heterocyclic group or the condensed ring are the same as defined for the substituents of the phenyl group, the C₃-C₈ cycloalkyl group, the aromatic heterocyclic aromatic group or the condensed ring in the above R¹, and the same examples are specifically preferable.

The remedially effective amount of the compounds represented by the above formula (I), pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C₁-C₆ alkyl-addition salts thereof together with a pharmaceutically acceptable carrier and/or a diluent can be prepared as a pharmaceutical composition and thus can be converted into medicines of the present invention capable of inhibiting the binding of chemokines to receptors on target cells, medicines having inhibitory actions on the binding of chemokines onto target cells or further remedies or prophylactics for diseases considered to be associated with chemokines or chemokine receptors. Namely, the cyclic amine derivatives represented by the above formula (I), pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C₁-C₆ alkyl addition salts thereof can be administered orally or parenterally such as intravenously, subcutaneously, intramuscularly, percutaneously or intrarectally.

For example, a tablet, a pill, a granule, a powder, a solution, a suspension or a capsule can be cited as the dosage form of the oral administration.

The tablet can be formed by using an vehicle, for example, lactose, starch or crystalline cellulose; a binder, for example, carboxymethylcellulose, methylcellulose or polyvinylpyrrolidone; or a disintegrator, for example, sodium alginate, sodium bicarbonate or sodium lauryl sulfate or the like according to a conventional method.

The pill, powder and granule can similarly be formed with using the above vehicle or the like according to a conventional method. The solution and suspension are produced with using glycerin esters, for example, tricaprylin or triacetin or alcohols, for example, ethanol according to a conventional method. The capsule is produced with filling a granule, powder or solution in a capsule such as gelatin.

A parenteral injection such as the form of an aqueous or a nonaqueous solution formulation is cited as the dosage form of subcutaneous, intramuscular or intravenous administration. For example, a isotonic sodium chloride solution is used as the aqueous solution. For example, propylene glycol, polyethylene glycol, olive oil or ethyl oleate is used for the nonaqueous solution. An antiseptic, a stabilizer or the like, if necessary, is added thereto. The parenteral injection is sterilized by suitably carrying out treatment such as filtration through a bacterial filter or combination of a disinfectant.

For example, an ointment or a cream is cited as the dosage form of percutaneous administration. The ointment is prepared by using oils and fats such as castor oil or olive oil or vaseline, and the cream is formed by using a fatty oil or an emulsifying agent such as diethylene glycol or sorbitan mono-fatty acid ester according to a conventional method.

A usual suppository such as a gelatin soft capsule is used for intrarectal administration.

The dose of the cyclic amine derivatives, pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C₁-C₆ alkyl addition salts thereof used in the present invention varies with the types of diseases, routs of administration, age and sex of patients and severity of diseases and the like, but is usually 1 to 500 mg/day for an adult.

Examples of the cyclic amine derivatives represented by the above formula (I) preferably include compounds having respective substituents shown in the following Tables 1.1 to 1.206

In Tables 1.1 to 1.206, “Table” means “Table”, and “Compd. No.” means “compound number”. “Chirality” means the “absolute configuration”, i.e. the absolute configuration of asymmetric carbon on the ring of the cyclic amine. “R” means that the asymmetric carbon atom on the ring of the cyclic amine has the absolute configuration of R, and “S” means that the asymmetric carbon atom has the absolute configuration of S. “-” means that the compound is a racemate or the compound has no asymmetric carbon atom on the cyclic amines.

TABLE 1.1 Compd.No.

k m n chirality R³

1

1 2 0 — H

2

1 2 0 — H

3

1 2 0 — H

4

1 2 0 — H

5

1 2 0 S H

6

1 2 0 S H

7

1 2 0 S H

8

1 2 0 S H

9

1 2 0 S H

10

1 2 0 S H

11

1 2 0 S H

TABLE 1.2 Compd.No.

k m n chirality R³

12

1 2 0 S H

13

1 2 0 S H

14

1 2 0 S H

15

1 2 0 S H

16

1 2 0 S H

17

1 2 0 S H

18

1 2 0 S H

19

1 2 0 S H

20

1 2 0 S H

21

1 2 0 S H

22

1 2 0 S H

TABLE 1.3 Compd.No.

k m n chirality R³

23

1 2 0 S H

24

1 2 0 S H

25

1 2 0 S H

26

1 2 0 S H

27

1 2 0 S H

28

1 2 0 S H

29

1 2 0 R H

30

1 2 0 R H

31

1 2 0 R H

32

1 2 0 R H

33

1 2 0 R H

TABLE 1.4 Compd.No.

k m n chirality R³

34

1 2 0 R H

35

1 2 0 R H

36

1 2 0 R H

37

1 2 0 R H

38

1 2 0 R H

39

1 2 0 R H

40

1 2 0 R H

41

1 2 0 R H

42

1 2 0 R H

43

1 2 0 R H

44

1 2 0 R H

TABLE 1.5 Compd.No.

k m n chirality R³

45

1 2 0 R H

46

1 2 0 R H

47

1 2 0 R H

48

1 2 0 R H

49

1 2 0 R H

50

1 2 0 R H

51

1 2 0 R H

52

1 2 0 R H

53

1 2 0 R H

54

1 2 0 R H

55

1 2 0 R H

TABLE 1.6 Compd.No.

k m n chirality R³

56

1 2 0 R H

57

1 2 0 R H

58

1 2 0 R H

59

1 2 0 R H

60

1 2 0 R H

61

1 2 0 R H

62

1 2 0 R H

63

1 2 0 R H

64

1 2 0 R H

65

1 2 0 R H

66

1 2 0 R H

TABLE 1.7 Compd.No.

k m n chirality R³

67

1 2 0 R H

68

1 2 0 R H

69

1 2 0 R H

70

1 2 0 R H

71

1 2 0 R H

72

1 2 0 R H

73

1 2 0 R H

74

1 2 0 R H

75

1 2 0 R H

76

1 2 0 R H

77

1 2 0 R H

TABLE 1.8 Compd.No.

k m n chirality R³

78

1 2 0 R H

79

1 2 0 R H

80

1 2 0 R H

81

1 2 0 R H

82

1 2 0 — —CH₃

83

1 2 0 R H

84

1 2 0 R H

85

1 2 0 — H

86

1 2 0 — H

87

1 2 0 S H

88

1 2 0 S H

TABLE 1.9 Compd.No.

k m n chirality R³

89

1 2 0 S H

90

1 2 0 S H

91

1 2 0 S H

92

1 2 0 S H

93

1 2 0 S H

94

1 2 0 S H

95

1 2 0 S H

96

1 2 0 S H

97

1 2 0 S H

98

1 2 0 S H

99

1 2 0 S H

TABLE 1.10 Compd.No.

k m n chirality R³

100

1 2 0 S H

101

1 2 0 S H

102

1 2 0 S H

103

1 2 0 S H

104

1 2 0 S H

105

1 2 0 S H

106

1 2 0 S H

107

1 2 0 S H

108

1 2 0 S H

109

1 2 0 S H

110

1 2 0 S H

TABLE 1.11 Compd.No.

k m n chirality R³

111

1 2 0 R H

112

1 2 0 R H

113

1 2 0 R H

114

1 2 0 R H

115

1 2 0 R H

116

1 2 0 R H

117

1 2 0 R H

118

1 2 0 R H

119

1 2 0 R H

120

1 2 0 R H

121

1 2 0 R H

TABLE 1.12 Compd. No.

k m n chirality R³

122

1 2 0 R H

123

1 2 0 R H

124

1 2 0 R H

125

1 2 0 R H

126

1 2 0 R H

127

1 2 0 R H

128

1 2 0 R H

129

1 2 0 R H

130

1 2 0 R H

131

1 2 0 R H

132

1 2 0 R H

TABLE 1.13 Compd. No.

k m n chirality R³

133

1 2 0 R H

134

1 2 0 R H

135

1 2 0 R H

136

1 2 0 R H

137

1 2 0 R H

138

1 2 0 R H

139

1 2 0 R H

140

1 2 0 R H

141

1 2 0 R H

142

1 2 0 R H

143

1 2 0 R H

TABLE 1.14 Compd. No.

k m n chirality R³

144

1 2 0 R H

145

1 2 0 R H

146

1 2 0 R H

147

1 2 0 R H

148

1 2 0 R H

149

1 2 0 R H

150

1 2 0 R H

151

1 2 0 R H

152

1 2 0 R H

153

1 2 0 R H

154

1 2 0 R H

TABLE 1.15 Compd. No.

k m n chirality R³

155

1 2 0 R H

156

1 2 0 R H

157

1 2 0 R H

158

1 2 0 R H

159

1 2 0 R H

160

1 2 0 R H

161

1 2 0 R H

162

1 2 0 R H

163

1 2 0 R H

164

1 2 0 R H

165

1 2 0 R H

TABLE 1.16 Compd. No.

k m n chirality R³

166

1 2 0 R H

167

1 2 0 R H

168

1 2 0 R H

169

1 2 0 R H

170

1 2 0 R H

171

1 2 0 R H

172

1 2 0 R H

173

1 2 0 R H

174

1 2 0 R H

175

1 2 0 R H

176

1 2 0 R H

TABLE 1.17 Compd. No.

k m n chirality R³

177

1 2 0 R H

178

1 2 0 R H

179

1 2 0 R H

180

1 2 0 R H

181

1 2 0 R H

182

1 2 0 R H

183

1 2 0 R H

184

1 2 0 R H

185

1 2 0 R H

186

1 2 0 R H

187

1 2 0 R H

TABLE 1.18 Compd. No.

k m n chirality R³

188

1 2 0 R H

189

1 2 0 R H

190

1 2 0 R H

191

1 2 0 R H

192

1 2 0 R H

193

1 2 0 R H

194

1 2 0 R H

195

1 2 0 R H

196

1 2 0 R H

197

1 2 0 R H

198

1 2 0 R H

TABLE 1.19 Compd. No.

k m n chirality R³

199

1 2 0 R H

200

1 2 0 R H

201

1 2 0 R H

202

1 2 0 R H

203

1 2 0 R H

204

1 2 0 R H

205

1 2 0 R H

206

1 2 0 R H

207

1 2 0 R H

208

1 2 0 R H

209

1 2 0 R H

TABLE 1.20 Compd. No.

k m n chirality R³

210

1 2 0 R H

211

1 2 0 R H

212

1 2 0 R H

213

1 2 0 R H

214

1 2 0 — H

215

1 2 0 — H

216

1 2 0 — H

217

1 2 0 — H

218

1 2 0 — H

219

1 2 0 — H

220

1 2 0 — H

TABLE 1.21 Compd. No.

k m n chirality R³

221

1 2 0 — H

222

1 2 0 — H

223

1 2 0 — H

224

1 2 0 — H

225

1 2 0 — H

226

1 2 0 — H

227

1 2 0 — H

228

1 2 0 — H

229

1 2 0 — H

230

1 2 0 — H

231

1 2 0 — H

TABLE 1.22 Compd. No.

k m n chirality R³

232

1 2 0 — H

233

1 2 0 — H

234

1 2 0 — H

235

1 2 0 — H

236

1 2 0 — H

237

1 2 0 — H

238

1 2 0 — H

239

1 2 0 S H

240

1 2 0 S H

241

1 2 0 S H

242

1 2 0 S H

TABLE 1.23 Compd. No.

k m n chirality R³

243

1 2 0 S H

244

1 2 0 S H

245

1 2 0 S H

246

1 2 0 S H

247

1 2 0 S H

248

1 2 0 S H

249

1 2 0 S H

250

1 2 0 S H

251

1 2 0 S H

252

1 2 0 S H

253

1 2 0 S H

TABLE 1.24 Compd. No.

k m n chirality R³

254

1 2 0 S H

255

1 2 0 S H

256

1 2 0 S H

257

1 2 0 S H

258

1 2 0 S H

259

1 2 0 S H

260

1 2 0 S H

261

1 2 0 S H

262

1 2 0 S H

263

1 2 0 S H

264

1 2 0 S H

TABLE 1.25 Compd. No.

k m n chirality R³

265

1 2 0 S H

266

1 2 0 S H

267

1 2 0 S H

268

1 2 0 S H

269

1 2 0 S H

270

1 2 0 S H

271

1 2 0 S H

272

1 2 0 S H

273

1 2 0 S H

274

1 2 0 S H

275

1 2 0 S H

TABLE 1.26 Compd. No.

k m n chirality R³

276

1 2 0 S H

277

1 2 0 S H

278

1 2 0 S H

279

1 2 0 S H

280

1 2 0 S H

281

1 2 0 S H

282

1 2 0 S H

283

1 2 0 S H

284

1 2 0 S H

285

1 2 0 R H

286

1 2 0 R H

TABLE 1.27 Compd.No.

k m n chirality R³

287

1 2 0 R H

288

1 2 0 R H

289

1 2 0 R H

290

1 2 0 R H

291

1 2 0 R H

292

1 2 0 R H

293

1 2 0 R H

294

1 2 0 R H

295

1 2 0 R H

296

1 2 0 R H

297

1 2 0 R H

TABLE 1.28 Compd.No.

k m n chirality R³

298

1 2 0 R H

299

1 2 0 R H

300

1 2 0 R H

301

1 2 0 R H

302

1 2 0 R H

303

1 2 0 R H

304

1 2 0 R H

305

1 2 0 R H

306

1 2 0 R H

307

1 2 0 R H

308

1 2 0 R H

TABLE 1.29 Compd.No.

k m n chirality R³

309

1 2 0 R H

310

1 2 0 R H

311

1 2 0 R H

312

1 2 0 R H

313

1 2 0 R H

314

1 2 0 R H

315

1 2 0 R H

316

1 2 0 R H

317

1 2 0 R H

318

1 2 0 R H

319

1 2 0 R H

TABLE 1.30 Compd.No.

k m n chirality R³

320

1 2 0 R H

321

1 2 0 R H

322

1 2 0 R H

323

1 2 0 R H

324

1 2 0 R H

325

1 2 0 R H

326

1 2 0 R H

327

1 2 0 R H

328

1 2 0 R H

329

1 2 0 R H

330

0 3 1 — H

TABLE 1.31 Compd.No.

k m n chirality R³

331

0 3 1 — H

332

0 3 1 — H

333

0 3 1 — H

334

0 3 1 — H

335

0 3 1 — H

336

0 3 1 — H

337

0 3 1 — H

338

0 3 1 — H

339

0 3 1 R H

340

0 3 1 S H

341

0 3 1 — H

TABLE 1.32 Compd.No.

k m n chirality R³

342

0 3 1 — H

343

0 3 1 — H

344

0 3 1 — H

345

0 3 1 — H

346

0 3 1 — H

347

0 3 1 — H

348

0 3 1 — H

349

0 3 1 — H

350

0 3 1 — H

351

0 3 1 — H

352

0 3 1 — H

TABLE 1.33 Compd.No.

k m n chirality R³

353

1 2 1 — H

354

1 3 0 — H

355

1 3 0 — H

356

1 3 0 — H

357

1 3 0 — H

358

1 3 0 — H

359

1 3 0 — H

360

1 3 0 — H

361

1 3 0 — H

362

1 3 0 — H

363

1 3 0 — H

TABLE 1.34 Compd.No.

k m n chirality R³

364

1 3 0 — H

365

1 3 0 — H

366

1 3 0 — H

367

1 3 0 — H

368

1 3 0 — H

369

1 3 0 — H

370

1 3 0 — H

371

1 3 0 — H

372

1 3 0 — H

373

1 3 0 — H

374

1 3 0 — H

TABLE 1.35 Compd.No.

k m n chirality R³

375

1 3 0 — H

376

1 3 0 — H

377

1 3 0 — H

378

1 3 0 — H

379

1 3 0 — H

380

1 3 0 — H

381

1 3 0 — H

382

1 3 0 — H

383

1 3 0 — H

384

2 2 0 — H

385

2 2 0 — H

TABLE 1.36 Compd.No.

k m n chirality R³

386

2 2 0 — H

387

2 2 0 — H

388

2 2 0 — H

389

2 2 0 — H

390

2 2 0 — H

391

2 2 0 — H

392

2 2 0 — H

393

2 2 0 — H

394

2 2 0 — H

395

2 2 0 — H

396

2 2 0 — H

TABLE 1.37 Compd.No.

k m n chirality R³

397

2 2 0 — H

398

2 2 0 — H

399

2 2 0 — H

400

2 2 0 — H

401

2 2 0 — H

402

2 2 0 — H

403

2 2 0 — H

404

2 2 0 — H

405

2 2 0 — H

406

2 2 0 — H

407

2 2 0 — H

TABLE 1.38 Compd.No.

k m n chirality R³

408

2 2 0 — H

409

2 2 0 — H

410

2 2 0 — H

411

2 2 0 — H

412

2 2 0 — H

413

2 2 0 — H

414

2 2 0 — H

415

2 2 0 — H

416

2 2 0 — H

417

2 2 0 — H

418

2 2 0 — H

TABLE 1.39 Compd.No.

k m n chirality R³

419

2 2 0 — H

420

2 2 0 — H

421

2 2 0 — H

422

2 2 0 — H

423

2 2 0 — H

424

2 2 0 — H

425

2 2 0 — H

426

2 2 0 — H

427

2 2 0 — H

428

2 2 0 — H

429

2 2 0 — H

TABLE 1.40 Compd.No.

k m n chirality R³

430

2 2 0 — H

431

2 2 0 — H

432

2 2 0 — H

433

2 2 0 — H

434

1 3 1 — H

435

1 3 1 — H

436

1 3 1 — H

437

1 3 1 — H

438

1 3 1 — H

439

1 3 1 — H

440

1 3 1 — H

TABLE 1.41 Compd.No.

k m n chirality R³

441

1 3 1 — H

442

1 3 1 — H

443

1 3 1 — H

444

1 3 1 — H

445

1 3 1 — H

446

1 3 1 — H

447

1 3 1 — H

448

1 3 1 — H

449

1 3 1 — H

450

1 3 1 — H

451

1 3 1 — H

TABLE 1.42 Compd.No.

k m n chirality R³

452

1 3 1 — H

453

1 3 1 — H

454

1 3 1 — H

455

1 3 1 — H

456

1 3 1 — H

457

1 3 1 — H

458

2 2 1 — H

459

2 2 1 — H

460

2 2 1 — H

461

2 2 1 — H

462

2 2 1 — H

TABLE 1.43 Compd.No.

k m n chirality R³

463

2 2 1 — H

464

2 2 1 — H

465

2 2 1 — H

466

2 2 1 — H

467

2 2 1 — H

468

2 2 1 — H

469

2 2 1 — H

470

2 2 1 — H

471

2 2 1 — H

472

2 2 1 — H

473

2 2 1 — H

TABLE 1.44 Compd.No.

k m n chirality R³

474

2 2 1 — H

475

2 2 1 — H

476

2 2 1 — H

477

2 2 1 — H

478

2 2 1 — H

479

2 2 1 — H

480

2 2 1 — H

481

2 2 1 — H

482

2 2 1 — H

483

2 2 1 — H

484

2 2 1 — H

TABLE 1.45 Compd.No.

k m n chirality R³

485

2 2 1 — H

486

2 2 1 — H

487

2 2 1 — H

488

2 2 1 — H

489

2 2 1 — H

490

2 2 1 — H

491

2 2 1 — H

492

2 2 1 — H

493

2 2 1 — H

494

2 2 1 — H

495

2 2 1 — H

TABLE 1.46 Compd.No.

k m n chirality R³

496

2 2 1 — H

497

2 2 1 — H

498

2 2 1 — H

499

2 2 1 — H

500

2 2 1 — H

501

2 2 1 — H

502

2 2 1 — H

503

2 2 1 — H

504

2 2 1 — H

505

2 2 1 — H

506

2 2 1 — H

TABLE 1.47 Compd.No.

k m n chirality R³

507

2 2 1 — H

508

2 2 1 — H

509

2 2 1 — H

510

2 2 1 — H

511

2 2 1 — H

512

2 2 1 — H

513

2 2 1 — H

514

2 2 1 — H

515

2 2 1 — H

516

2 2 1 — H

517

2 2 1 — H

TABLE 1.48 Compd.No.

k m n chirality R³

518

2 2 1 — H

519

2 2 1 — H

520

2 2 1 — —CH₃

521

2 2 1 —

522

2 2 1 —

523

2 2 1 —

524

2 2 1 —

525

2 2 1 — H

526

2 2 1 — H

527

2 2 1 — H

528

2 2 1 — H

TABLE 1.49 Compd.No.

k m n chirality R³

529

2 2 1 — H

530

2 2 1 — H

531

2 2 1 — H

532

2 2 1 — H

533

2 2 1 — H

534

2 2 1 — H

535

2 2 1 — H

536

2 2 1 — H

537

2 2 1 — H

538

2 2 1 — H

539

2 2 1 — H

TABLE 1.50 Compd.No.

k m n chirality R³

540

2 2 1 — H

541

2 2 1 — H

542

2 2 1 — H

543

2 2 1 — H

544

2 2 1 — H

545

2 2 1 — H

546

2 2 1 — H

547

2 2 1 — H

548

2 2 1 — H

549

2 2 1 — H

550

2 2 1 — H

TABLE 1.51 Compd.No.

k m n chirality R³

551

2 2 1 — H

552

2 2 1 — H

553

2 2 1 — H

554

2 2 1 — H

555

2 2 1 — H

556

2 2 1 — H

557

2 2 1 — H

558

2 2 1 — H

559

2 2 1 — H

560

2 2 1 — H

561

2 2 1 — H

TABLE 1.52 Compd.No.

k m n chirality R³

562

2 2 1 — H

563

2 2 1 — H

564

2 2 1 — H

565

2 2 1 — H

566

2 2 1 — H

567

2 2 1 — H

568

2 2 1 — H

569

2 2 1 — H

570

2 2 1 — H

571

2 2 1 — H

572

2 2 1 — H

TABLE 1.53 Compd.No.

k m n chirality R³

573

2 2 1 — H

574

2 2 1 — H

575

2 2 1 — H

576

2 2 1 — H

577

2 2 1 — H

578

2 2 1 — H

579

2 2 1 — H

580

2 2 1 — H

581

2 2 1 — H

582

2 2 1 — H

583

2 2 1 — H

TABLE 1.54 Compd.No.

k m n chirality R³

584

2 2 1 — H

585

2 2 1 — H

586

2 2 1 — H

587

2 2 1 — H

588

2 2 1 — H

589

2 2 1 — H

590

2 2 1 — H

591

2 2 1 — H

592

2 2 1 — H

593

2 2 1 — H

594

2 2 1 — H

TABLE 1.55 Compd.No.

k m n chirality R³

595

2 2 1 — H

596

2 2 1 — H

597

2 2 1 — H

598

2 2 1 — H

599

2 2 1 — H

600

2 2 1 — H

601

2 2 1 — H

602

2 2 1 — H

603

2 2 1 — H

604

2 2 1 — H

605

2 2 1 — H

TABLE 1.56 Compd.No.

k m n chirality R³

606

2 2 1 — H

607

2 2 1 — H

608

2 2 1 — H

609

2 2 1 — H

610

2 2 1 — H

611

2 2 1 — H

612

2 2 1 — H

613

2 2 1 — H

614

2 2 1 — H

615

2 2 1 — H

616

2 2 1 — H

TABLE 1.57 Compd.No.

k m n chirality R³

617

2 2 1 — H

618

2 2 1 — H

619

2 2 1 — H

620

2 2 1 — H

621

2 2 1 — H

622

2 2 1 — H

623

2 2 1 — H

624

2 2 1 — H

625

2 2 1 — H

626

2 2 1 — H

627

2 2 1 — H

TABLE 1.58 Compd.No.

k m n chirality R³

628

2 2 1 — H

629

2 2 1 — H

630

2 2 1 — H

631

2 2 1 — H

632

2 2 1 — H

633

2 2 1 — H

634

2 2 1 — H

635

2 2 1 — H

636

2 2 1 — H

637

2 2 1 — H

638

2 2 1 — H

TABLE 1.59 Compd.No.

k m n chirality R³

639

2 2 1 — H

640

2 2 1 — H

641

2 2 1 — H

642

2 2 1 — H

643

2 2 1 — H

644

2 2 1 — H

645

2 2 1 — H

646

2 2 1 — H

647

2 2 1 — H

648

2 2 1 — H

649

2 2 1 — H

TABLE 1.60 Compd.No.

k m n chirality R³

650

2 2 1 — H

651

2 2 1 — H

652

2 2 1 — H

653

2 2 1 — H

654

2 2 1 — H

655

2 2 1 — H

656

2 2 1 — H

657

2 2 1 — H

658

2 2 1 — H

659

2 2 1 — H

660

2 2 1 — H

TABLE 1.61 Compd.No.

k m n chirality R³

661

2 2 1 — H

662

2 2 1 — H

663

2 2 1 — H

664

2 2 1 — H

665

2 2 1 — H

666

2 2 1 — H

667

2 2 1 — H

668

2 2 1 — H

669

2 2 1 — H

670

2 2 1 — H

671

2 2 1 — H

TABLE 1.62 Compd.No.

k m n chirality R³

672

2 2 1 — H

673

2 2 1 — H

674

2 2 1 — H

675

2 2 1 — H

676

2 2 1 — H

677

2 2 1 — H

678

2 2 1 — H

679

2 2 1 — H

680

2 2 1 — H

681

2 2 1 — H

682

2 2 1 — H

TABLE 1.63 Compd.No.

k m n chirality R³

683

2 2 1 — H

684

2 2 1 — H

685

2 2 1 — H

686

2 2 1 — H

687

2 2 1 — H

688

2 2 1 — H

689

2 2 1 — H

690

2 2 1 — H

691

2 2 1 — H

692

2 2 1 — H

693

2 2 1 — H

TABLE 1.64 Compd.No.

k m n chirality R³

694

2 2 1 — H

695

2 2 1 — H

696

2 2 1 — H

697

2 2 1 — H

698

2 2 1 — H

699

2 2 1 — H

700

2 2 1 — H

701

2 2 1 — H

702

2 2 1 — H

703

2 2 1 — H

704

2 2 1 — H

TABLE 1.65 Compd.No.

k m n chirality R³

705

2 2 1 — H

706

2 2 1 — H

707

2 2 1 — H

708

2 2 1 — H

709

2 2 1 — H

710

2 2 1 — H

711

2 2 1 — H

712

2 2 1 — H

713

2 2 1 — H

714

2 2 1 — H

715

2 2 1 — H

TABLE 1.66 Compd.No.

k m n chirality R³

716

2 2 1 — H

717

2 2 1 — H

718

2 2 1 — H

719

2 2 1 — H

720

2 2 1 — H

721

2 2 1 — H

722

2 2 1 — H

723

2 2 1 — H

724

2 2 1 — H

725

2 2 1 — H

726

2 2 1 — H

TABLE 1.67 Compd.No.

k m n chirality R³

727

2 2 1 — H

728

2 2 1 — H

729

2 2 1 — H

730

2 2 1 — H

731

2 2 1 — H

732

2 2 1 — H

733

2 2 1 — H

734

2 2 1 — H

735

2 2 1 — H

736

2 2 1 — H

737

2 2 1 — H

TABLE 1.68 Compd.No.

k m n chirality R³

738

2 2 1 — H

739

2 2 1 — H

740

2 2 1 — H

741

2 2 1 — H

742

2 2 1 — H

743

2 2 1 — H

744

2 2 1 — H

745

2 2 1 — H

746

2 2 1 — H

747

2 2 1 — H

748

2 2 1 — H

TABLE 1.69 Compd.No.

k m n chirality R³

749

2 2 1 — H

750

2 2 1 — H

751

2 2 1 — H

752

2 2 1 — H

753

2 2 1 — H

754

2 2 1 — H

755

2 2 1 — H

756

2 2 1 — H

757

2 2 1 — H

758

2 2 1 — H

759

2 2 1 — H

TABLE 1.70 Compd.No.

k m n chirality R³

760

2 2 1 — H

761

2 2 1 — H

762

2 2 1 — H

763

2 2 1 — H

764

2 2 1 — H

765

2 2 1 — H

766

2 2 1 — H

767

2 2 1 — H

768

2 2 1 — H

769

2 2 1 — H

770

2 2 1 — H

TABLE 1.71 Compd.No.

k m n chirality R³

771

2 2 1 — H

772

2 2 1 — H

773

2 2 1 — H

774

2 2 1 — H

775

2 2 1 — H

776

2 2 1 — H

777

2 2 1 — H

778

2 2 1 — H

779

2 2 1 — H

780

2 2 1 — H

781

2 2 1 — H

TABLE 1.72 Compd.No.

k m n chirality R³

782

2 2 1 — H

783

2 2 1 — H

784

2 2 1 — H

785

2 2 1 — H

786

2 2 1 — H

787

2 2 1 — H

788

2 2 1 — H

789

2 2 1 — H

790

2 2 1 — H

791

2 2 1 — H

792

2 2 1 — H

TABLE 1.73 Compd.No.

k m n chirality R³

793

2 2 1 — H

794

2 2 1 — H

795

2 2 1 — H

796

2 2 1 — H

797

2 2 1 — H

798

2 2 1 — H

799

2 2 1 — H

800

2 2 1 — H

801

2 2 1 — H

802

2 2 1 — H

803

2 2 1 — H

TABLE 1.74 Compd.No.

k m n chirality R³

804

2 2 1 — H

805

2 2 1 — H

806

2 2 1 — H

807

2 2 1 — H

808

2 2 1 — H

809

2 2 1 — H

810

2 2 1 — H

811

2 2 1 — H

812

2 2 1 — H

813

2 2 1 — H

814

2 2 1 — H

TABLE 1.75 Compd.No.

k m n chirality R³

815

2 2 1 — H

816

2 2 1 — H

817

2 2 1 — H

818

2 2 1 — H

819

2 2 1 — H

820

2 2 1 — H

821

2 2 1 — H

822

2 2 1 — H

823

2 2 1 — H

824

2 2 1 — H

825

2 2 1 — H

TABLE 1.76 Compd.No.

k m n chirality R³

826

2 2 1 — H

827

2 2 1 — H

828

2 2 1 — H

829

2 2 1 — H

830

2 2 1 — H

831

2 2 1 — H

832

2 2 1 — H

833

2 2 1 — H

834

2 2 1 — H

835

2 2 1 — H

836

2 2 1 — H

TABLE 1.77 Compd.No.

k m n chirality R³

837

2 2 1 — H

838

2 2 1 — H

839

2 2 1 — H

840

2 2 1 — H

841

2 2 1 — H

842

2 2 1 — H

843

2 2 1 — H

844

2 2 1 — H

845

2 2 1 — H

846

2 2 1 — H

847

2 2 1 — H

TABLE 1.78 Compd.No.

k m n chirality R³

848

2 2 1 — H

849

2 2 1 — H

850

2 2 1 — H

851

2 2 1 — H

852

2 2 1 — H

853

2 2 1 — H

854

2 2 1 — H

855

2 2 1 — H

856

2 2 1 — H

857

2 2 1 — H

858

2 2 1 — H

TABLE 1.79 Compd.No.

k m n chirality R³

859

2 2 1 — H

860

2 2 1 — H

861

2 2 1 — H

862

2 2 1 — H

863

2 2 1 — H

864

2 2 1 — H

865

2 2 1 — H

866

2 2 1 — H

867

2 2 1 — H

868

2 2 1 — H

869

2 2 1 — H

TABLE 1.80 Compd.No.

k m n chirality R³

870

2 2 1 — H

871

2 2 1 — H

872

2 2 1 — H

873

2 2 1 — H

874

2 2 1 — H

875

2 2 1 — H

876

2 2 1 — H

877

2 2 1 — H

878

2 2 1 — H

879

2 2 1 — H

880

2 2 1 — H

TABLE 1.81 Compd.No.

k m n chirality R³

881

2 2 1 — H

882

2 2 1 — H

883

2 2 1 — H

884

2 2 1 — H

885

2 2 1 — H

886

2 2 1 — H

887

2 2 1 — H

888

2 2 1 — H

889

2 2 1 — H

890

2 2 1 — H

891

2 2 1 — H

TABLE 1.82 Compd.No.

k m n chirality R³

892

2 2 1 — H

893

2 2 1 — H

894

2 2 1 — H

895

2 2 1 — H

896

2 2 1 — H

897

2 2 1 — H

898

2 2 1 — H

899

2 2 1 — H

900

2 2 1 — H

901

2 2 1 — H

902

2 2 1 — H

TABLE 1.83 Compd.No.

k m n chirality R³

903

2 2 1 — H

904

2 2 1 — H

905

2 2 1 — H

906

2 2 1 — H

907

2 2 1 — H

908

2 2 1 — H

909

2 2 1 — H

910

2 2 1 — H

911

2 2 1 — H

912

2 2 1 — H

913

2 2 1 — H

TABLE 1.84 Compd.No.

k m n chirality R³

914

2 2 1 — H

915

2 2 1 — H

916

2 2 1 — H

917

2 2 1 — H

918

2 2 1 — H

919

2 2 1 — H

920

2 2 1 — H

921

2 2 1 — H

922

2 2 1 — H

923

2 2 1 — H

924

2 2 1 — H

TABLE 1.85 Compd.No.

k m n chirality R³

925

2 2 1 — H

926

2 2 1 — H

927

2 2 1 — H

928

2 2 1 — H

929

2 2 1 — H

930

2 2 1 — H

931

2 2 1 — H

932

2 2 1 — H

933

2 2 1 — H

934

2 2 1 — H

935

2 2 1 — H

TABLE 1.86 Compd.No.

k m n chirality R³

936

2 2 1 — H

937

2 2 1 — H

938

2 2 1 — H

939

2 2 1 — H

940

2 2 1 — H

941

2 2 1 — H

942

2 2 1 — H

943

1 4 0 — H

944

1 4 0 — H

945

1 4 0 — H

946

1 4 0 — H

TABLE 1.87 Compd.No.

k m n chirality R³

947

1 4 0 — H

948

1 4 0 — H

949

1 4 0 — H

950

0 4 1 — H

951

1 2 0 R H

952

1 2 0 R H

953

1 2 0 R H

954

1 2 0 R H

955

1 2 0 R H

956

1 2 0 R H

957

1 2 0 R H

TABLE 1.88 Compd.No.

k m n chirality R³

958

1 2 0 R H

959

1 2 0 R H

960

1 2 0 R H

961

1 2 0 R H

962

1 2 0 R H

963

1 2 0 R H

964

1 2 0 R H

965

1 2 0 R H

966

1 2 0 R H

967

1 2 0 R H

968

1 2 0 R H

TABLE 1.89 Compd.No.

k m n chirality R³

969

1 2 0 R H

970

1 2 0 R H

971

1 2 0 R H

972

1 2 0 R H

973

1 2 0 R H

974

1 2 0 R H

975

1 2 0 R H

976

1 2 0 R H

977

1 2 0 R H

978

1 2 0 R H

979

1 2 0 R H

TABLE 1.90 Compd.No.

k m n chirality R³

980

1 2 0 R H

981

1 2 0 R H

982

1 2 0 R H

983

1 2 0 R H

984

1 2 0 R H

985

1 2 0 R H

986

1 2 0 R H

987

2 2 1 — H

988

1 4 0 — H

989

1 4 0 — H

990

1 4 0 — H

TABLE 1.91 Compd.No.

k m n chirality R³

991

1 4 0 — H

992

1 4 0 — H

993

1 4 0 — H

994

1 4 0 — H

995

1 4 0 — H

996

1 4 0 — H

997

2 2 1 — H

998

2 2 1 — H

999

2 2 1 — H

1000 

2 2 1 — H

1001 

2 2 1 — H

TABLE 1.92 Compd.No.

k m n chirality R³

1002

2 2 1 — H

1003

2 2 1 — H

1004

2 2 1 — H

1005

2 2 1 — H

1006

2 2 1 — H

1007

2 2 1 — H

1008

2 2 1 — H

1009

2 2 1 — H

1010

2 2 1 — H

1011

2 2 1 — H

1012

2 2 1 — H

TABLE 1.93 Compd.No.

k m n chirality R³

1013

2 2 1 — H

1014

2 2 1 — H

1015

2 2 1 — H

1016

2 2 0 — H

1017

2 2 0 — H

1018

2 2 1 — H

1019

2 2 1 — H

1020

2 2 1 — H

1021

2 2 1 — H

1022

2 2 1 — H

1023

2 2 1 — H

TABLE 1.94 Compd.No.

k m n chirality R³

1024

2 2 1 — H

1025

2 2 1 — H

1026

2 2 1 — H

1027

2 2 1 — H

1028

2 2 1 — H

1029

2 2 1 — H

1030

2 2 1 — H

1031

2 2 1 — H

1032

2 2 1 — H

1033

2 2 1 — H

1034

2 2 1 — H

TABLE 1.95 Compd.No.

k m n chirality R³

1035

2 2 1 — H

1036

2 2 1 — H

1037

2 2 1 — H

1038

2 2 1 — H

1039

2 2 1 — H

1040

2 2 1 — H

1041

2 2 1 — H

1042

2 2 1 — H

1043

2 2 1 — H

1044

2 2 1 — H

1045

2 2 1 — H

TABLE 1.96 Compd.No.

k m n chirality R³

1046

2 2 1 — H

1047

2 2 1 — H

1048

2 2 1 — H

1049

2 2 1 — H

1050

2 2 1 — H

1051

2 2 1 — H

1052

2 2 1 — H

1053

2 2 1 — H

1054

2 2 1 — H

1055

2 2 1 — H

1056

2 2 1 — H

TABLE 1.97 Compd.No.

k m n chirality R³

1057

2 2 1 — H

1058

2 2 1 — H

1059

2 2 1 — H

1060

2 2 1 — H

1061

2 2 1 — H

1062

2 2 1 — H

1063

2 2 1 — H

1064

2 2 1 — H

1065

2 2 1 — H

1066

2 2 1 — H

1067

2 2 1 — H

TABLE 1.98 Compd.No.

k m n chirality R³

1068

2 2 1 — H

1069

2 2 1 — H

1070

2 2 1 — H

1071

2 2 1 — H

1072

2 2 1 — H

1073

2 2 1 — H

1074

2 2 1 — H

1075

2 2 1 — H

1076

2 2 1 — H

1077

2 2 1 — H

1078

2 2 1 — H

TABLE 1.99 Compd.No.

k m n chirality R³

1079

2 2 1 — H

1080

2 2 1 — H

1081

2 2 1 — H

1082

2 2 1 — H

1083

2 2 1 — H

1084

1 2 0 R H

1085

1 2 0 R H

1086

1 2 0 R H

1087

1 2 0 R H

1088

1 2 0 R H

1089

1 2 0 R H

TABLE 1.100 Compd.No.

k m n chirality R³

1090

1 2 0 R H

1091

1 2 0 R H

1092

1 2 0 R H

1093

1 2 0 R H

1094

1 2 0 R H

1095

1 2 0 R H

1096

1 2 0 R H

1097

1 2 0 R H

1098

1 2 0 R H

1099

1 2 0 R H

1100

1 2 0 R H

TABLE 1.101 Compd.No.

k m n chirality R³

1101

1 2 0 R H

1102

1 2 0 R H

1103

1 2 0 R H

1104

1 2 0 R H

1105

1 2 0 R H

1106

1 2 0 R H

1107

1 2 0 R H

1108

1 2 0 R H

1109

1 2 0 R H

1110

1 2 0 R H

1111

1 2 0 R H

TABLE 1.102 Compd.No.

k m n chirality R³

1112

1 2 0 R H

1113

2 2 1 — H

1114

2 2 1 — H

1115

2 2 1 — H

1116

2 2 1 — H

1117

2 2 1 — H

1118

1 2 0 R H

1119

1 2 0 R H

1120

1 2 0 R H

1121

1 2 0 R H

1122

1 2 0 R H

TABLE 1.103 Compd.No.

k m n chirality R³

1123

1 2 0 R H

1124

1 2 0 R H

1125

2 2 1 — H

1126

2 2 1 — H

1127

2 2 1 — H

1128

2 2 1 — H

1129

2 2 1 — H

1130

2 2 1 — H

1131

2 2 1 — H

1132

2 2 1 — H

1133

1 2 0 R H

TABLE 1.104 Compd.No.

k m n chirality R³

1134

1 2 0 R H

1135

1 2 0 R H

1136

1 2 0 R H

1137

1 2 0 R H

1138

1 2 0 R H

1139

1 2 0 R H

1140

1 2 0 R H

1141

1 2 0 R H

1142

1 2 0 R H

1143

1 2 0 R H

1144

1 2 0 R H

TABLE 1.105 Compd.No.

k m n chirality R³

1145

1 2 0 R H

1146

1 2 0 R H

1147

1 2 0 R H

1148

1 2 0 R H

1149

1 2 0 R H

1150

1 2 0 R H

1151

1 2 0 R H

1152

1 2 0 R H

1153

1 2 0 R H

1154

1 2 0 R H

1155

1 2 0 R H

TABLE 1.106 Compd.No.

k m n chirality R³

1156

1 2 0 R H

1157

1 2 0 R H

1158

1 2 0 R H

1159

1 2 0 R H

1160

1 2 0 R H

1161

1 2 0 R H

1162

1 2 0 R H

1163

1 2 0 R H

1164

1 2 0 R H

1165

1 2 0 R H

1166

1 2 0 R H

TABLE 1.107 Compd.No.

k m n chirality R³

1167

2 2 1 — H

1168

1 2 0 R H

1169

1 2 0 R H

1170

1 2 0 R H

1171

1 2 0 R H

1172

1 2 0 R H

1173

1 2 0 R H

1174

1 2 0 R H

1175

1 2 0 R H

1176

1 2 0 R H

1177

1 2 0 R H

TABLE 1.108 Compd.No.

k m n chirality R³

1178

1 2 0 R H

1179

1 2 0 R H

1180

1 2 0 R H

1181

1 2 0 R H

1182

1 2 0 R H

1183

1 2 0 R H

1184

1 2 0 R H

1185

1 2 0 R H

1186

1 2 0 R H

1187

2 2 1 — H

1188

2 2 1 — H

TABLE 1.109 Compd.No.

k m n chirality R³

1189

2 2 1 — H

1190

2 2 1 — H

1191

1 2 0 R H

1192

1 2 0 R H

1193

1 2 0 R H

1194

1 2 0 R H

1195

1 2 0 R H

1196

1 2 0 R H

1197

1 2 0 R H

1198

1 2 0 R H

1199

1 2 0 R H

TABLE 1.110 Compd.No.

k m n chirality R³

1200

1 2 0 R H

1201

1 2 0 R H

1202

1 2 0 R H

1203

1 2 0 R H

1204

1 2 0 R H

1205

1 2 0 R H

1206

1 2 0 R H

1207

1 2 0 R H

1208

1 2 0 R H

1209

1 2 0 R H

1210

1 2 0 R H

TABLE 1.111 Compd.No.

k m n chirality R³

1211

1 2 0 R H

1212

1 2 0 R H

1213

2 2 1 — H

1214

2 2 1 — H

1215

2 2 1 — H

1216

2 2 1 — H

1217

1 2 0 R H

1218

1 2 0 R H

1219

1 2 0 R H

1220

1 2 0 R H

1221

1 2 0 R H

TABLE 1.112 Compd.No.

k m n chirality R³

1222

1 2 0 R H

1223

1 2 0 R H

1224

1 2 0 R H

1225

1 2 0 R H

1226

1 2 0 R H

1227

1 2 0 R H

1228

1 2 0 R H

1229

1 2 0 R H

1230

1 2 0 R H

1231

1 2 0 R H

1232

1 2 0 R H

TABLE 1.113 Compd.No.

k m n chirality R³

1233

1 2 0 R H

1234

1 2 0 R H

1235

1 2 0 R H

1236

1 2 0 R H

1237

1 2 0 R H

1238

1 2 0 R H

1239

1 2 0 R H

1240

1 2 0 R H

1241

2 2 1 — H

1242

2 2 1 — H

1243

2 2 1 — H

TABLE 1.114 Compd.No.

k m n chirality R³

1244

2 2 1 — H

1245

2 2 1 — H

1246

2 2 1 — H

1247

2 2 1 — H

1248

2 2 1 — H

1249

1 2 0 R H

1250

1 2 0 R H

1251

1 2 0 R H

1252

1 2 0 R H

1253

1 2 0 R H

1254

1 2 0 R H

TABLE 1.115 Compd.No.

k m n chirality R³

1255

1 2 0 R H

1256

1 2 0 R H

1257

1 2 0 R H

1258

1 2 0 R H

1259

1 2 0 R H

1260

1 2 0 R H

1261

1 2 0 R H

1262

1 2 0 R H

1263

1 2 0 R H

1264

1 2 0 R H

1265

1 2 0 R H

TABLE 1.116 Compd.No.

k m n chirality R³

1266

1 2 0 R H

1267

1 2 0 R H

1268

1 2 0 R H

1269

1 2 0 R H

1270

1 2 0 R H

1271

1 2 0 R H

1272

1 2 0 R H

1273

1 2 0 R H

1274

1 2 0 R H

1275

1 2 0 R H

1276

1 2 0 R H

TABLE 1.117 Compd.No.

k m n chirality R³

1277

1 2 0 R H

1278

1 2 0 R H

1279

1 2 0 R H

1280

1 2 0 R H

1281

1 2 0 R H

1282

2 2 1 — H

1283

2 2 1 — H

1284

2 2 1 — H

1285

2 2 1 — H

1286

1 2 0 R H

1287

1 2 0 R H

TABLE 1.118 Compd.No.

k m n chirality R³

1288

1 2 0 R H

1289

1 2 0 R H

1290

1 2 0 R H

1291

1 2 0 R H

1292

1 2 0 R H

1293

1 2 0 R H

1294

1 2 0 R H

1295

1 2 0 R H

1296

1 2 0 R H

1297

1 2 0 R H

1298

1 2 0 R H

TABLE 1.119 Compd.No.

k m n chirality R³

1299

1 2 0 R H

1300

1 2 0 R H

1301

1 2 0 R H

1302

1 2 0 R H

1303

1 2 0 R H

1304

1 2 0 R H

1305

1 2 0 R H

1306

1 2 0 R H

1307

1 2 0 R H

1308

1 2 0 R H

1309

1 2 0 R H

TABLE 1.120 Compd.No.

k m n chirality R³

1310

1 2 0 R H

1311

1 2 0 R H

1312

1 2 0 R H

1313

1 2 0 R H

1314

1 2 0 R H

1315

1 2 0 R H

1316

1 2 0 R H

1317

1 2 0 R H

1318

1 2 0 R H

1319

1 2 0 R H

1320

1 2 0 R H

TABLE 1.121 Compd.No.

k m n chirality R³

1321

1 2 0 R H

1322

1 2 0 R H

1323

1 2 0 R H

1324

1 2 0 R H

1325

1 2 0 R H

1326

1 2 0 R H

1327

1 2 0 R H

1328

1 2 0 R H

1329

1 2 0 R H

1330

1 2 0 R H

1331

1 2 0 R H

TABLE 1.122 Compd.No.

k m n chirality R³

1332

1 2 0 R H

1333

1 2 0 R H

1334

1 2 0 R H

1335

1 2 0 R H

1336

1 2 0 R H

1337

1 2 0 R H

1338

1 2 0 R H

1339

1 2 0 R H

1340

1 2 0 R H

1341

1 2 0 R H

1342

2 2 1 — H

TABLE 1.123 Compd.No.

k m n chirality R³

1343

2 2 1 — H

1344

2 2 1 — H

1345

2 2 1 — H

1346

2 2 1 — H

1347

1 2 0 R H

1348

1 2 0 R H

1349

1 2 0 R H

1350

2 2 1 — H

1351

1 2 0 R H

1352

1 2 0 R H

1353

1 2 0 R H

TABLE 1.124 Compd.No.

k m n chirality R³

1354

2 2 1 — H

1355

1 2 0 R H

1356

1 2 0 R H

1357

1 2 0 R H

1358

2 2 1 — H

1359

1 2 0 R H

1360

1 2 0 R H

1361

1 2 0 R H

1362

1 2 0 R H

1363

1 2 0 R H

1364

1 2 0 R H

TABLE 1.125 Compd.No.

k m n chirality R³

1365

1 2 0 R H

1366

1 2 0 R H

1367

1 2 0 R H

1368

1 2 0 R H

1369

1 2 0 R H

1370

1 2 0 R H

1371

1 2 0 R H

1372

1 2 0 R H

1373

1 2 0 R H

1374

1 2 0 R H

1375

1 2 0 R H

TABLE 1.126 Compd.No.

k m n chirality R³

1376

1 2 0 R H

1377

1 2 0 R H

1378

1 2 0 R H

1379

1 2 0 R H

1380

1 2 0 R H

1381

1 2 0 R H

1382

1 2 0 R H

1383

2 2 1 — H

1384

2 2 1 — H

1385

2 2 1 — H

1386

2 2 1 — H

TABLE 1.127 Compd.No.

k m n chirality R³

1387

1 2 0 R H

1388

1 2 0 R H

1389

1 2 0 R H

1390

1 2 0 R H

1391

1 2 0 R H

1392

1 2 0 R H

1393

1 2 0 R H

1394

1 2 0 R H

1395

1 2 0 R H

1396

1 2 0 R H

1397

1 2 0 R H

TABLE 1.127 Compd.No.

k m n chirality R³

1398

1 2 0 R H

1399

1 2 0 R H

1400

1 2 0 R H

1401

1 2 0 R H

1402

1 2 0 R H

1403

1 2 0 R H

1404

1 2 0 R H

1405

1 2 0 R H

1406

1 2 0 R H

1407

1 2 0 R H

1408

1 2 0 R H

TABLE 1.129 Compd.No.

k m n chirality R³

1409

1 2 0 R H

1410

1 2 0 R H

1411

1 2 0 R H

1412

1 2 0 R H

1413

1 2 0 R H

1414

2 2 1 — H

1415

1 2 0 R H

1416

1 2 0 R H

1417

1 2 0 R H

1418

2 2 1 — H

1419

1 2 0 R H

TABLE 1.130 Compd.No.

k m n chirality R³

1420

1 2 0 R H

1421

1 2 0 R H

1422

2 2 1 — H

1423

1 2 0 R H

1424

1 2 0 R H

1425

1 2 0 R H

1426

2 2 1 — H

1427

2 2 1 — H

1428

2 2 1 — H

1429

2 2 1 — H

1430

2 2 1 — H

TABLE 1.131 Compd.No.

k m n chirality R³

1431

2 2 1 — H

1432

2 2 1 — H

1433

2 2 1 — H

1434

2 2 1 — H

1435

2 2 1 — H

1436

2 2 1 — H

1437

2 2 1 — H

1438

2 2 1 — H

1439

2 2 1 — H

1440

2 2 1 — H

1441

2 2 1 — H

TABLE 1.132 Compd. No.

k m n chirality R³

1442

2 2 1 — H

1443

2 2 1 — H

1444

2 2 1 — H

1445

2 2 1 — H

1446

2 2 1 — H

1447

2 2 1 — H

1448

2 2 1 — H

1449

2 2 1 — H

1450

2 2 1 — H

1451

2 2 1 — H

1452

2 2 1 — H

TABLE 1.133 Compd. No.

k m n chirality R³

1453

2 2 1 — H

1454

2 2 1 — H

1455

2 2 1 — H

1456

2 2 1 — H

1457

2 2 1 — H

1458

2 2 1 — H

1459

2 2 1 — H

1460

2 2 1 — H

1461

2 2 1 — H

1462

2 2 1 — H

1463

2 1 1 — H

TABLE 1.134 Compd. No.

k m n chirality R³

1464

2 1 1 — H

1465

2 1 1 — H

1466

2 1 1 — H

1467

2 1 1 — H

1468

2 1 1 — H

1469

2 1 1 — H

1470

2 1 1 — H

1471

2 1 1 — H

1472

1 2 0 R H

1473

1 2 0 R H

1474

1 2 0 R H

TABLE 1.135 Compd. No.

k m n chirality R³

1475

1 2 0 R H

1476

1 2 0 R H

1477

1 2 0 R H

1478

1 2 0 R H

1479

1 2 0 R H

1480

1 2 0 R H

1481

1 2 0 R H

1482

1 2 0 R H

1483

1 2 0 R H

1484

1 2 0 R H

1485

1 2 0 R H

TABLE 1.136 Compd. No.

k m n chirality R³

1486

1 2 0 R H

1487

1 2 0 R H

1488

1 2 0 R H

1489

1 2 0 R H

1490

1 2 0 R H

1491

1 2 0 R H

1492

1 2 0 R H

1493

1 2 0 R H

1494

1 2 0 R H

1495

1 2 0 R H

1496

1 2 0 R H

TABLE 1.137 Compd. No.

k m n chirality R³

1497

1 2 0 R H

1498

1 2 0 R H

1499

1 2 0 R H

1500

1 2 0 R H

1501

1 2 0 R H

1502

1 2 0 R H

1503

1 2 0 R H

1504

1 2 0 R H

1505

1 2 0 R H

1506

2 1 1 — H

1507

2 1 1 — H

TABLE 1.138 Compd. No.

k m n chirality R³

1508

2 1 1 — H

1509

2 1 1 — H

1510

2 1 1 — H

1511

2 1 1 — H

1512

2 1 1 — H

1513

2 1 1 — H

1514

2 2 1 — H

1515

2 2 1 — H

1516

2 2 1 — H

1517

2 2 1 — H

1518

2 2 1 — H

TABLE 1.139 Compd. No.

k m n chirality R³

1519

2 2 1 — H

1520

1 2 0 R H

1521

1 2 0 R H

1522

1 2 0 R H

1523

1 2 0 R H

1524

1 2 0 R H

1525

1 2 0 R H

1526

1 2 0 R H

1527

1 2 0 R H

1528

1 2 0 R H

1529

1 2 0 R H

TABLE 1.140 Compd. No.

k m n chirality R³

1530

1 2 0 R H

1531

1 2 0 R H

1532

1 2 0 R H

1533

1 2 0 R H

1534

1 2 0 R H

1535

1 2 0 R H

1536

1 2 0 R H

1537

1 2 0 R H

1538

1 2 0 R H

1539

1 2 0 R H

1540

1 2 0 R H

TABLE 1.141 Compd. No.

k m n chirality R³

1541

1 2 0 R H

1542

1 2 0 R H

1543

1 2 0 R H

1544

1 2 0 R H

1545

1 2 0 R H

1546

1 2 0 R H

1547

1 2 0 R H

1548

1 2 0 R H

1549

1 2 0 R H

1550

1 2 0 R H

1551

1 2 0 R H

TABLE 1.142 Compd. No.

k m n chirality R³

1552

1 2 0 R H

1553

1 2 0 R H

1554

1 2 0 R H

1555

1 2 0 R H

1556

1 2 0 R H

1557

1 2 0 R H

1558

1 2 0 R H

1559

1 2 0 R H

1560

1 2 0 R H

1561

1 2 0 R H

1562

1 2 0 R H

TABLE 1.143 Compd. No.

k m n chirality R³

1563

1 2 0 R H

1564

1 2 0 R H

1565

1 2 0 R H

1566

1 2 0 R H

1567

1 2 0 R H

1568

1 2 0 R H

1569

1 2 0 R H

1570

2 2 1 — H

1571

2 2 1 — H

1572

2 2 1 — H

1573

2 2 1 — H

TABLE 1.144 Compd. No.

k m n chirality R³

1574

2 2 1 — H

1575

2 2 1 — H

1576

2 2 1 — H

1577

2 2 1 — H

1578

2 2 1 — H

1579

2 2 1 — H

1580

2 2 1 — H

1581

2 2 1 — H

1582

2 2 1 — H

1583

1 2 0 R H

1584

1 2 0 R H

TABLE 1.145 Compd. No.

k m n chirality R³

1585

1 2 0 R H

1586

1 2 0 R H

1587

1 2 0 R H

1588

1 2 0 R H

1589

1 2 0 R H

1590

1 2 0 R H

1591

1 2 0 R H

1592

1 2 0 R H

1593

1 2 0 R H

1594

1 2 0 R H

1595

1 2 0 R H

TABLE 1.146 Compd. No.

k m n chirality R³

1596

1 2 0 R H

1597

1 2 0 R H

1598

1 2 0 R H

1599

1 2 0 R H

1600

2 2 1 — H

1601

2 2 1 — H

1602

2 2 1 — H

1603

2 2 1 — H

1604

2 2 1 — H

1605

2 2 1 — H

1606

1 2 0 R H

TABLE 1.147 Compd.No.

k m n chirality R³

1607

1 2 0 R H

1608

1 2 0 R H

1609

2 2 1 — H

1610

2 2 1 — H

1611

2 2 1 — H

1612

2 2 1 — H

1613

2 2 1 — H

1614

1 2 0 R H

1615

2 2 1 — H

1616

2 2 1 — H

1617

2 2 1 — H

TABLE 1.148 Compd.No.

k m n chirality R³

1618

1 2 0 R H

1619

1 2 0 R H

1620

1 2 0 R H

1621

1 2 0 R H

1622

1 2 0 R H

1623

1 2 0 R H

1624

1 2 0 R H

1625

1 2 0 R H

1626

1 2 0 R H

1627

1 2 0 R H

1628

1 2 0 R H

TABLE 1.149 Compd.No.

k m n chirality R³

1629

1 2 0 R H

1630

1 2 0 R H

1631

1 2 0 R H

1632

1 2 0 R H

1633

1 2 0 R H

1634

1 2 0 R H

1635

1 2 0 R H

1636

1 2 0 R H

1637

1 2 0 R H

1638

1 2 0 R H

1639

1 2 0 R H

TABLE 1.150 Compd.No.

k m n chirality R³

1640

1 2 0 R H

1641

1 2 0 R H

1642

1 2 0 R H

1643

1 2 0 R H

1644

1 2 0 R H

1645

1 2 0 R H

1646

1 2 0 R H

1647

2 2 1 — H

1648

1 2 0 R H

1649

2 2 1 — H

1650

1 2 0 R H

TABLE 1.151 Compd.No.

k m n chirality R³

1651

2 2 1 — H

1652

2 2 1 — H

1653

2 2 1 — H

1654

2 2 1 — H

1655

2 2 1 — H

1656

2 2 1 — H

1657

2 2 1 — H

1658

2 2 1 — H

1659

2 2 1 — H

1660

1 2 0 R H

1661

1 2 0 R H

TABLE 1.152 Compd.No.

k m n chirality R³

1662

1 2 0 R H

1663

1 2 0 R H

1664

2 2 1 R H

1665

2 2 1 R H

1666

2 2 1 R H

1667

2 2 1 R H

1668

2 2 1 R H

1669

2 2 1 R H

1670

2 2 1 R H

1671

2 2 1 R H

1672

2 2 1 R H

TABLE 1.153 Compd.No.

k m n chirality R³

1673

2 2 1 — H

1674

2 2 1 — H

1675

2 2 1 — H

1676

2 2 1 — H

1677

2 2 1 — H

1678

2 2 1 — H

1679

2 2 1 — H

1680

2 2 1 — H

1681

2 2 1 — H

1682

2 2 1 — H

1683

2 2 1 — H

TABLE 1.154 Compd.No.

k m n chirality R³

1684

2 2 1 — H

1685

2 2 1 — H

1686

2 2 1 — H

1687

2 2 1 — H

1688

2 2 1 — H

1689

2 2 1 — H

1690

2 2 1 — H

1691

2 2 1 — H

1692

1 2 0 R H

1693

1 2 0 R H

1694

1 2 0 R H

TABLE 1.155 Compd.No.

k m n chirality R³

1695

2 2 1 R H

1696

2 2 1 R H

1697

2 2 1 R H

1698

2 2 1 R H

1699

2 2 1 R H

1700

2 2 1 R H

1701

2 2 1 R H

1702

2 2 1 R H

1703

1 2 0 R H

1704

1 2 0 R H

1705

1 2 0 R H

TABLE 1.156 Compd.No.

k m n chirality R³

1706

1 2 0 R H

1707

1 2 0 R H

1708

1 2 0 R H

1709

1 2 0 R H

1710

1 2 0 R H

1711

1 2 0 R H

1712

1 2 0 R H

1713

1 2 0 R H

1714

1 2 0 R H

1715

1 2 0 R H

1716

1 2 0 R H

TABLE 1.157 Compd.No.

k m n chirality R³

1717

1 2 0 R H

1718

1 2 0 R H

1719

1 2 0 R H

1720

1 2 0 R H

1721

1 2 0 R H

1722

1 2 0 R H

1723

1 2 0 R H

1724

1 2 0 R H

1725

1 2 0 R H

1726

1 2 0 R H

1727

1 2 0 R H

TABLE 1.158 Compd.No.

k m n chirality R³

1728

1 2 0 R H

1729

1 2 0 R H

1730

1 2 0 R H

1731

1 2 0 R H

1732

1 2 0 R H

1733

1 2 0 R H

1734

1 2 0 R H

1735

1 2 0 R H

1736

1 2 0 R H

1737

1 2 0 R H

1738

1 2 0 R H

TABLE 1.159 Compd.No.

k m n chirality R³

1739

1 2 0 R H

1740

1 2 0 R H

1741

1 2 0 R H

1742

1 2 0 R H

1743

1 2 0 R H

1744

1 2 0 R H

1745

1 2 0 R H

1746

1 2 0 R H

1747

1 2 0 R H

1748

1 2 0 R H

1749

1 2 0 R H

TABLE 1.160 Compd.No.

k m n chirality R³

1750

1 2 0 R H

1751

1 2 0 R H

1752

1 2 0 R H

1753

1 2 0 R H

1754

1 2 0 R H

1755

1 2 0 R H

1756

1 2 0 R H

1757

1 2 0 R H

1758

1 2 0 R H

1759

1 2 0 R H

1760

1 2 0 R H

TABLE 1.161 Compd.No.

k m n chirality R³

1761

1 2 0 R H

1762

1 2 0 R H

1763

1 2 0 R H

1764

1 2 0 R H

1765

1 2 0 R H

1766

1 2 0 R H

1767

1 2 0 R H

1768

1 2 0 R H

1769

1 2 0 R H

1770

1 2 0 R H

1771

1 2 0 R H

TABLE 1.162 Compd. No.

k m n chirality R³

1772

1 2 0 R H

1773

1 2 0 R H

1774

1 2 0 R H

1775

1 2 0 R H

1776

1 2 0 R H

1777

2 2 1 — H

1778

2 2 1 — H

1779

2 2 1 — H

1780

2 2 1 — H

1781

2 2 1 — H

1782

2 2 1 — H

TABLE 1.163 Compd. No.

k m n chirality R³

1783

2 2 1 — H

1784

2 2 1 — H

1785

2 2 1 — H

1786

2 2 1 — H

1787

1 2 0 R H

1788

2 2 1 — H

1789

2 2 1 — H

1790

1 2 0 S H

1791

1 2 0 S H

1792

2 2 1 — H

1793

2 2 1 — H

TABLE 1.164 Compd. No.

k m n chirality R³

1794

2 2 1 — H

1795

2 2 1 — H

1796

2 2 1 — H

1797

2 2 1 — H

1798

2 2 1 — H

1799

2 2 1 — H

1800

2 2 1 — H

1801

2 2 1 — H

1802

1 2 0 R H

1803

1 2 0 R H

1804

2 2 1 — H

TABLE 1.165 Compd. No.

k m n chirality R³

1805

1 2 0 R H

1806

1 2 0 R H

1807

1 2 0 R H

1808

1 2 0 R H

1809

1 2 0 R H

1810

1 2 0 R H

1811

1 2 0 R H

1812

1 2 0 R H

1813

1 2 0 R H

1814

1 2 0 R H

1815

1 2 0 R H

TABLE 1.166 Compd. No.

k m n chirality R³

1816

1 2 0 R H

1817

1 2 0 R H

1818

1 2 0 R H

1819

1 2 0 R H

1820

1 2 0 R H

1821

1 2 0 R H

1822

1 2 0 R H

1823

1 2 0 R H

1824

1 2 0 R H

1825

1 2 0 R H

1826

1 2 0 R H

TABLE 1.167 Compd. No.

k m n chirality R³

1827

1 2 0 R H

1828

1 2 0 R H

1829

1 2 0 R H

1830

1 2 0 R H

1831

1 2 0 R H

1832

1 2 0 R H

1833

1 2 0 R H

1834

1 2 0 R H

1835

1 2 0 R H

1836

1 2 0 R H

1837

1 2 0 R H

TABLE 1.168 Compd. No.

k m n chirality R³

1838

1 2 0 R H

1839

1 2 0 R H

1840

1 2 0 R H

1841

1 2 0 R H

1842

1 2 0 R H

1843

1 2 0 R H

1844

1 2 0 R H

1845

1 2 0 R H

1846

1 2 0 R H

1847

1 2 0 R H

1848

1 2 0 R H

TABLE 1.169 Compd. No.

k m n chirality R³

1849

1 2 0 R H

1850

1 2 0 R H

1851

1 2 0 R H

1852

1 2 0 R H

1853

1 2 0 R H

1854

1 2 0 R H

1855

1 2 0 R H

1856

1 2 0 R H

1857

1 2 0 R H

1858

1 2 0 R H

1859

1 2 0 R H

TABLE 1.170 Compd. No.

k m n chirality R³

1860

1 2 0 R H

1861

1 2 0 R H

1862

1 2 0 R H

1863

1 2 0 R H

1864

1 2 0 R H

1865

1 2 0 R H

1866

1 2 0 R H

1867

1 2 0 R H

1868

1 2 0 R H

1869

1 2 0 R H

1870

1 2 0 R H

TABLE 1.171 Compd. No.

k m n chirality R³

1871

1 2 0 R H

1872

1 2 0 R H

1873

1 2 0 R H

1874

1 2 0 R H

18751

1 2 0 R H

1876

1 2 0 R H

1877

1 2 0 R H

1878

1 2 0 R H

1879

1 2 0 R H

1880

1 2 0 R H

1881

1 2 0 R H

TABLE 1.172 Compd. No.

k m n chirality R³

1882

1 2 0 R H

1883

1 2 0 R H

1884

1 2 0 R H

1885

1 2 0 R H

1886

1 2 0 R H

1887

1 2 0 R H

1888

1 2 0 R H

1889

1 2 0 R H

1890

1 2 0 R H

1891

1 2 0 R H

1892

1 2 0 R H

TABLE 1.173 Compd. No.

k m n chirality R³

1893

1 2 0 R H

1894

1 2 0 R H

1895

1 2 0 R H

1896

1 2 0 R H

1897

1 2 0 R H

1898

1 2 0 R H

1899

1 2 0 R H

1900

1 2 0 R H

1901

1 2 0 R H

1902

1 2 0 R H

1903

2 2 1 — H

TABLE 1.174 Compd. No.

k m n chirality R³

1904

2 2 1 — H

1905

1 2 0 R H

1906

1 2 0 R H

1907

1 2 0 R H

1908

1 2 0 R H

1909

1 2 0 R H

1910

2 2 1 — H

1911

2 2 1 — H

1912

2 2 1 — H

1913

2 2 1 — H

1914

2 2 1 — H

TABLE 1.175 Compd. No.

k m n chirality R³

1915

1 2 0 R H

1916

1 2 0 R H

1917

2 2 1 — H

1918

2 2 1 — H

1919

2 2 1 — H

1920

2 2 1 — H

1921

1 2 0 R H

1922

2 2 1 — H

1923

2 2 1 — H

1924

2 2 1 — H

1925

2 2 1 — H

TABLE 1.176 Compd. No.

k m n chirality R³

1926

2 2 1 — H

1927

2 2 1 — H

1928

2 2 1 — H

1929

2 2 1 — H

1930

2 2 1 — H

1931

2 2 1 — H

1932

2 2 1 — H

1933

2 2 1 — H

1934

2 2 1 — H

1935

2 2 1 — H

1936

2 2 1 — H

TABLE 1.177 Compd.No.

k m n chirality R³

1937

2 2 1 — H

1938

2 2 1 — H

1939

2 2 1 — H

1940

2 2 1 — H

1941

2 2 1 — H

1942

2 2 1 — H

1943

2 2 1 — H

1944

2 2 1 — H

1945

2 2 1 — H

1946

2 2 1 — H

1947

2 2 1 — H

TABLE 1.178 Compd.No.

k m n chirality R³

1948

2 2 1 — H

1949

2 2 1 — H

1950

2 2 1 — H

1951

2 2 1 — H

1952

2 2 1 — H

1953

2 2 1 — H

1954

2 2 1 — H

1955

2 2 1 — H

1956

2 2 1 — H

1957

2 2 1 — H

1958

2 2 1 — H

TABLE 1.179 Compd.No.

k m n chirality R³

1959

2 2 1 — H

1960

2 2 1 — H

1961

2 2 1 — H

1962

2 2 1 — H

1963

2 2 1 — H

1964

2 2 1 — H

1965

2 2 1 — H

1966

2 2 1 — H

1967

2 2 1 — H

1968

2 2 1 — H

1969

2 2 1 — H

TABLE 1.180 Compd.No.

k m n chirality R³

1970

2 2 1 — H

1971

2 2 1 — H

1972

2 2 1 — H

1973

2 2 1 — H

1974

2 2 1 — H

1975

2 2 1 — H

1976

2 2 1 — H

1977

2 2 1 — H

1978

2 2 1 — H

1979

2 2 1 — H

1980

2 2 1 — H

TABLE 1.181 Compd.No.

k m n chirality R³

1981

2 2 1 — H

1982

2 2 1 — H

1983

2 2 1 — H

1984

2 2 1 — H

1985

2 2 1 — H

1986

2 2 1 — H

1987

2 2 1 — H

1988

2 2 1 — H

1989

2 2 1 — H

1990

2 2 1 — H

1991

2 2 1 — H

TABLE 1.182 Compd.No.

k m n chirality R³

1992

2 2 1 — H

1993

2 2 1 — H

1994

2 2 1 — H

1995

2 2 1 — H

1996

2 2 1 — H

1997

2 2 1 — H

1998

2 2 1 — H

1999

2 2 1 — H

2000

2 2 1 — H

2001

2 2 1 — H

2002

2 2 1 — H

TABLE 1.183 Compd.No.

k m n chirality R³

2003

2 2 1 — H

2004

2 2 1 — H

2005

2 2 1 — H

2006

2 2 1 — H

2007

2 2 1 — H

2008

2 2 1 — H

2009

2 2 1 — H

2010

2 2 1 — H

2011

2 2 1 — H

2012

2 2 1 — H

2013

2 2 1 — H

TABLE 1.184 Compd.No.

k m n chirality R³

2014

2 2 1 — H

2015

2 2 1 — H

2016

2 2 1 — H

2017

2 2 1 — H

2018

2 2 1 — H

2019

2 2 1 — H

2020

2 2 1 — H

2021

2 2 1 — H

2022

2 2 1 — H

2023

2 2 1 — H

2024

2 2 1 — H

TABEL 1.185 Compd.No.

k m n chirality R³

2025

2 2 1 — H

2026

2 2 1 — H

2027

2 2 1 — H

2028

2 2 1 — H

2029

2 2 1 — H

2030

2 2 1 — H

2031

2 2 1 — H

2032

2 2 1 — H

2033

2 2 1 — H

2034

2 2 1 — H

2035

2 2 1 — H

TABLE 1.186 Compd.No.

k m n chirality R³

2036

2 2 1 — H

2037

2 2 1 — H

2038

2 2 1 — H

2039

2 2 1 — H

2040

1 2 0 R H

2041

1 2 0 R H

2042

1 2 0 R H

2043

1 2 0 R H

2044

1 2 0 R H

2045

1 2 0 R H

2046

1 2 0 R H

TABLE 1.187 Compd.No.

k m n chirality R³

2047

1 2 0 R H

2048

1 2 0 R H

2049

1 2 0 R H

2050

1 2 0 R H

2051

1 2 0 R H

2052

2 2 1 — H

2053

2 2 1 — H

2054

2 2 1 — H

2055

2 2 1 — H

2056

2 2 1 — H

2057

2 2 1 — H

TABLE 1.188 Compd.No.

k m n chirality R³

2058

2 2 1 — H

2059

2 2 1 — H

2060

2 2 1 — H

2061

2 2 1 — H

2062

2 2 1 — H

2063

2 2 1 — H

2064

2 2 1 — H

2065

2 2 1 — H

2066

2 2 1 — H

2067

2 2 1 — H

2068

2 2 1 — H

TABLE 1.189 Compd.No.

k m n chirality R³

2069

2 2 1 — H

2070

2 2 1 — H

2071

2 2 1 — H

2072

2 2 1 — H

2073

2 2 1 — H

2074

2 2 1 — H

2075

2 2 1 — H

2076

2 2 1 — H

2077

2 2 1 — H

2078

2 2 1 — H

2079

2 2 1 — H

TABLE 1.190 Compd.No.

k m n chirality R³

2080

2 2 1 — H

2081

2 2 1 — H

2082

2 2 1 — H

2083

1 2 0 R H

2084

1 2 0 R H

2085

1 2 0 R H

2086

1 2 0 R H

2087

1 2 0 R H

2088

1 2 0 R H

2089

1 2 0 R H

2090

1 2 0 R H

TABLE 1.191 Compd.No.

k m n chirality R³

2091

2 2 1 — H

2092

2 2 1 — H

2093

2 2 1 — H

2094

2 2 1 — H

2095

2 2 1 — H

2096

2 2 1 — H

2097

2 2 1 — H

2098

2 2 1 — H

2099

2 2 1 — H

2100

2 2 1 — H

2101

2 2 1 — H

TABLE 1.192 Compd.No.

k m n chirality R³

2102

2 2 1 — H

2103

2 2 1 — H

2104

2 2 1 — H

2105

2 2 1 — H

2106

2 2 1 — H

2107

2 2 1 — H

2108

2 2 1 — H

2109

2 2 1 — H

2110

2 2 1 — H

2111

2 2 1 — H

2112

2 2 1 — H

TABLE 1.193 Compd.No.

k m n chirality R³

2113

2 2 1 — H

2114

2 2 1 — H

2115

2 2 1 — H

2116

2 2 1 — H

2117

2 2 1 — H

2118

1 2 0 R H

2119

1 2 0 R H

2120

1 2 0 R H

2121

1 2 0 R H

2122

1 2 0 R H

2123

1 2 0 R H

TABLE 1.194 Compd.No.

k m n chirality R³

2124

1 2 0 R H

2125

1 2 0 R H

2126

1 2 0 R H

2127

1 2 0 R H

2128

1 2 0 R H

2129

1 2 0 R H

2130

2 2 1 — H

2131

2 2 1 — H

2132

1 2 0 R H

2133

1 2 0 R H

2134

1 2 0 R H

TABLE 1.195 Compd.No.

k m n chirality R³

2135

1 2 0 R H

2136

1 2 0 R H

2137

1 2 0 R H

2138

1 2 0 R H

2139

1 2 0 R H

2140

2 2 1 — H

2141

2 2 1 — H

2142

2 2 1 — H

2143

2 2 1 — H

2144

2 2 1 — H

2145

2 2 1 — H

TABLE 1.196 Compd.No.

k m n chirality R³

2146

2 2 1 — H

2147

2 2 1 — H

2148

2 2 1 — H

2149

1 2 0 R H

2150

1 2 0 R H

2151

1 2 0 R H

2152

1 2 0 R H

2153

1 2 0 R H

2154

2 2 1 — H

2155

2 2 1 — H

2156

2 2 1 — H

TABLE 1.197 Compd.No.

k m n chirality R³

2157

1 2 0 R H

2158

1 2 0 R H

2159

2 2 1 — H

2160

2 2 1 — H

2161

2 2 1 — H

2162

2 2 1 — H

2163

2 2 1 — H

2164

1 2 0 R H

2165

1 2 0 R H

2166

1 2 0 R H

2167

1 2 0 R H

TABLE 1.198 Compd.No.

k m n chirality R³

2168

1 2 0 R H

2169

1 2 0 R H

2170

1 2 0 R H

2171

1 2 0 R H

2172

1 2 0 R H

2173

1 2 0 R H

2174

1 2 0 R H

2175

1 2 0 R H

2176

1 2 0 R H

2177

1 2 0 R H

2178

1 2 0 R H

TABLE 1.199 Compd.No.

k m n chirality R³

2179

1 2 0 R H

2180

1 2 0 R H

2181

1 2 0 R H

2182

1 2 0 R H

2183

1 2 0 R H

2184

2 2 1 — H

2185

2 2 1 — H

2186

2 2 1 — H

2187

1 2 0 R H

2188

2 2 1 — H

2189

1 2 0 R H

TABLE 1.200 Compd.No.

k m n chirality R³

2190

2 2 1 — H

2191

2 2 1 — H

2192

2 2 1 — H

2193

2 2 1 — H

2194

2 2 1 — H

2195

2 2 1 — H

2196

1 2 0 R H

2197

1 2 0 R H

2198

1 2 0 R H

2199

2 2 1 — H

2200

2 2 1 — H

TABLE 1.201 Compd.No.

k m n chirality R³

2201

2 2 1 — H

2202

1 2 0 R H

2203

2 2 1 — H

2204

2 2 1 — H

2205

2 2 1 — H

2206

2 2 1 — H

2207

2 2 1 — H

2208

2 2 1 — H

2209

2 2 1 — H

2210

1 2 0 R H

2211

2 2 1 — H

TABLE 1.202 Compd.No.

k m n chirality R³

2212

2 2 1 — H

2213

2 2 1 — H

2214

2 2 1 — H

2215

1 2 0 R H

2216

1 2 0 R H

2217

1 2 0 R H

2218

1 2 0 R H

2219

1 2 0 R H

2220

1 2 0 R H

2221

1 2 0 R H

2222

1 2 0 R H

TABLE 1.203 Compd.No.

k m n chirality R³

2223

1 2 0 R H

2224

1 2 0 R H

2225

1 2 0 R H

2226

1 2 0 R H

2227

1 2 0 R H

2228

1 2 0 R H

2229

1 2 0 R H

2230

1 2 0 R H

2231

1 2 0 R H

2232

1 2 0 R H

2233

1 2 0 R H

TABLE 1.204 Compd.No.

k m n chirality R³

2234

1 2 0 R H

2235

1 2 0 R H

2236

1 2 0 R H

2237

1 2 0 R H

2238

1 2 0 R H

2239

1 2 0 R H

2240

1 2 0 R H

2241

1 2 0 R H

2242

1 2 0 R H

2243

1 2 0 R H

2244

1 2 0 R H

TABLE 1.205 Compd.No.

k m n chirality R³

2245

1 2 0 R H

2246

1 2 0 R H

2247

1 2 0 R H

2248

1 2 0 R H

2249

1 2 0 R H

2250

1 2 0 R H

2251

1 2 0 R H

2252

2 2 1 — H

2253

2 2 1 — H

2254

2 2 1 — H

2255

2 2 1 — H

TABLE 1.206 Compd.No.

k m n chirality R³

2256

2 2 1 — H

2257

2 2 1 — H

The acid addition salts of the cyclic amine compounds are also used in the present invention. Examples of the acid include a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or carbonic acid and an organic acid such as maleic acid, citric acid, malic acid, tartaric acid, fumaric acid, methanesulfonic acid, trifluoroacetic acid or formic acid.

Furthermore, C₁-C₆ alkyl addition salts of the cyclic amine compounds, for example, 1-(4-chlorobenzyl)-1-methyl-4-[{N-(3-trifluoromethylbenzoyl)glycyl}aminomethyl]piperidinium iodide are also used in the present invention. The alkyl group preferably includes methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, 2-methylpentyl and 1-ethylbutyl herein; however, methyl group, ethyl group or the like is especially preferable. A halide anion such as fluoride, chloride, bromide or iodide is preferable for a counter anion of an ammonium cation.

In the present invention, a racemate and all the possible optically active forms of the compounds represented by the above formula (I) can also be used.

The compounds represented by the above formula (I) can be synthesized by using any of the following general preparation processes described in WO9925686:

(Preparation Process 1)

A preparation process comprises reacting one equivalent of a compound represented by the following formula (II):

wherein R¹, R², R³, j, k, m and n are each the same as defined in the above formula (I), with 0.1 to 10 equivalents of a carboxylic acid represented by the following formula (III):

wherein R⁴, R⁵, R⁶, G, p and q are each the same as defined in the above formula (I), or a reactive derivative thereof in the absence or presence of a solvent.

The “reactive derivative” of the carboxylic acid represented by the above formula (III) mean a carboxylic acid derivative, for example, an acid halide, an acid anhydride or a mixed acid anhydride usually used in the synthetic organic chemistry field and having high reactivity.

The reaction can more smoothly be made to proceed by suitably using an adequate amount of a dehydrating agent such as molecular sieve; a coupling reagent such as dicyclohexylcarbodiimide (DCC), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDCI or WSC), carbonyldiimidazole (CDI), N-hydroxysuccinimide (HOSu), N-hydroxybenzotriazole (HOBt), benzotriazol-1-yloxytris(pyrrolidinol) phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-=(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(5-norbornene-2,3-dicarboxylmide)-1,1,3,3-tetramethyluronium tetrafluorobonite (TNTU), O-(N-succinimidyl)-1,1,3,3-tetramethyluronium hexafluorophosphate (TSTU) or bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBroP); a base such as an inorganic base such as potassium carbonate, calcium carbonate or sodium hydrogencarbonate; amines such as triethylamine, diisoproylethylamine or pyridine or a polymer supported base such as (piperidinomethyl)polystyrene, (morpholinomethyl)polystyrene, (dimethylaminomethyl)polystyrene or poly(4-vinylpyridine).

(Preparation process 2)

A preparation process comprises reacting one equivalent of an alkylating reagent represented by the following formula (IV):

wherein R¹, R² and j are each the same as defined in the above formula (I); X is a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group, with 0.1 to 10 equivalents of a compound represented by the following formula (V):

wherein R³, R⁴, R⁵, R⁶, G, k, m, n, p and q are each the same as defined in the above formula (I), in the absence or presence of a solvent.

The reaction can more smoothly be made to proceed by suitably using a base similar to that in the preparation process 1. Furthermore, the reaction sometimes can be promoted by the presence of an iodide such as potassium iodide or sodium iodide.

In the above formula (IV), X is a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group. Examples of the halogen atom preferably include a chlorine atom, a bromine atom and an iodine atom. Specific examples of the alkylsulfonyloxy group preferably include a methylsulfonyloxy group, a trifluoromethylsulfonyloxy group and the like, and the specific example of the arylsulfonyloxy group preferably includes tosyloxy group.

(Preparation process 3)

A preparation process comprises reacting one equivalent of an aldehyde represented by the following formula (VI):

wherein R¹ and R² are each the same as defined in the above formula (I); j is 1 or 2, or an aldehyde represented by the following formula (VII): R¹—CHO  (VII) wherein R¹ is the same as defined for R¹ in the above formula (I); the compound corresponds to the case where j is 0, with 0.1 to 10 equivalents of a compound represented by the above formula (V) in the absence or presence of a solvent.

The reaction is usually called a reductive amination reaction and a catalytic hydrogenation reaction using a catalyst containing a metal such as palladium, platinum, nickel or rhodium, a hydrogenation reaction using a complex hydride such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride and borane, an electrolytic reducing reaction or the like can be used as reductive conditions.

(Preparation process 4)

A preparation process comprises reacting one equivalent of a compound represented by the following formula (VIII):

wherein R¹, R², R³, R⁴, R⁵, R⁷, j, k, m, n, p and q are each the same as defined in the above formula (I), with 0.1 to 10 equivalents of a carboxylic acid or a sulfonic acid represented by the following formula (IX): HO—A—R⁶  (IX) wherein R⁶ is the same as defined in the above formula (I); A is a carbonyl group or a sulfonyl group, or a reactive derivative thereof in the absence or presence of a solvent.

The reactive derivative of the carboxylic acid or sulfonic acid represented by the above formula (IX) means a carboxylic acid derivative or sulfonic acid derivative, for example, an acid halide, an acid anhydride or a mixed acid anhydride usually used in the synthetic organic chemistry field and having high reactivity. The reaction can more smoothly be made to proceed by suitably using a dehydrating agent, a coupling reagent or a base similar to that in the above preparation process 1.

(Preparation Process 5)

A preparation process comprises reacting one equivalent of a compound represented by the above formula (VIII) with 0.1 to 10 equivalents of an isocyanate or an isothiocyanate represented by the following formula (X): Z═C═N—R⁶  (X) wherein R⁶ is the same as defined in the above formula (I); Z is an oxygen atom or a sulfur atom, in the absence or presence of a solvent. (Preparation process 6)

A preparation process comprises reacting one equivalent of a compound represented by the following formula (XI):

wherein R¹, R², R³, R⁴, R⁵, j, k, m, n, p and q are each the same as defined in the above formula (I); A is a carbonyl group or a sulfonyl group, with 0.1 to 10 equivalents of an amine represented by the following formula (XII): R⁶—NH₂  (XII) wherein R⁶ is the same as defined for R⁶ in the above formula (I), in the absence or presence of a solvent.

The reaction can more smoothly be made to proceed by suitably using a dehydrating agent, a coupling reagent or a base similar to that in the above preparation process 1.

In the above preparation processes 1 to 6, when a substrate used for each reaction has substitutents regarded as usually reacting under respective reaction conditions in the organic synthetic chemistry or having adverse effects on the reaction, the functional groups can be protected with a known suitable protecting group, and the substrate can be used for the reaction and then deprotected by a conventional known method to afford the objective compound.

In addition, the compounds used in the present invention can be obtained by further converting (single or plural) substituents of the compound produced by the above preparation process 1-6 using a known reaction usually used in the organic-synthetic chemistry, for example, an alkylation reaction, an acylation reaction or a reduction reaction.

In the above respective preparation processes, a halogenated hydrocarbon such as dichloromethane or chloroform, an aromatic hydrocarbon such as benzene or toluene, ethers such as diethyl ether or tetrahydrofuran, esters such as ethyl acetate, an aprotic polar solvent such as dimethylformamide, dimethyl sulfoxide or acetonitrile and alcohols such as methanol, ethanol or isopropyl alcohol are suitably used as a reaction solvent according to the reaction.

In each of the preparation processes, the reaction temperature is within the range of −78 to +150° C., preferably within the range of 0 to 100° C. After completing the reaction, the objective cyclic amine compounds represented by the above formula (I) can be isolated by carrying out usual isolating and purifying operations, i.e., concentration, filtration, extraction, solid-phase extraction, recrystallization or chromatography. The compounds can be converted into their pharmaceutically acceptable acid addition salts thereof or their C₁-C₆ alkyl addition salts thereof according to a usual method.

EXAMPLES

The present invention is detailed specifically based on Examples; however, the present invention is not restricted to compounds described in the Examples. The Compound number (Compd. No.) assigned to each compound in the following Examples corresponds to the Compd. No. assigned to each compound cited as a preferred specific example in Tables 1.1 to 1.206.

Reference Example 1 Synthesis of 3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride

4-Chlorobenzyl chloride (4.15 g, 25.8 mmol) and ^(i)Pr₂NEt (6.67 g, 51.6 mmol) were added to a DMF (50 mL) solution of 3-[(tert-butoxycarbonyl)amino]pyrrolidine (4.81 g, 25.8 mmol). The reaction mixture was stirred at 70° C. for 15 hours, and the solvent was removed under reduced pressure. The objective 3-[(tert-butoxycarbonyl)amino]-1-(4-chlorobenzyl)pyrrolidine (6.43 g, 80%) was obtained as an off-white solid by recrystallization (acetonitrile, 50 mL). ¹H NMR (CDCl₃, 300 MHz) δ 1.37 (s, 9H), 1.5-1.7 (br, 1H), 2.1-2.4 (m, 2H), 2.5-2.7 (m, 2H), 2.83 (br, 1H), 3.57 (s, 2H), 4.1-4.3 (br, 1H), 4.9-5.1 (br, 1H), 7.15-7.35 (br, 4H); the purity was determined by RPLC/MS (98%). ESI/MS m/e 311.0 (M⁺+H, C₁₆H₂₄ClN₂O₂).

To a methanol solution (80 mL) of the 3-[(tert-butoxycarbonyl)amino]-1-(4-chlorobenzyl)pyrrolidine (6.38 g, 20.5 mmol), was added 1 M HCl-Et₂O (100 mL). The resulting mixture was stirred at 25° C. for 15 hours. The solvent was removed under reduced pressure to provide a solid, which was purified by recrystallization (methanol/acetonitrile=1:2, 130 mL) to thereby afford 3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride (4.939 g, 85%) as a white powder. ¹H NMR (d₆-DMSO, 300 MHz) δ 3.15 (br, 1H), 3.3-3.75 (br-m, 4H), 3.9 (br, 1H), 4.05 (br, 1H), 4.44 (br, 1H), 4.54 (br, 1H), 7.5-7.7 (m, 4H), 8.45 (br, 1H), 8.60 (br, 1H); the purity was determined by RPLC/MS (>99%). ESI/MS m/e 211.0 (M⁺+H, C₁₁H₁₆ClN₂).

Optically active (R)-3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride and (S)-3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride were synthesized by using the respective corresponding starting materials according to the above method. The products exhibited the same ¹H NMR as that of the above racemate.

Example 1 Synthesis of 3-(N-benzoylglycyl)amino-1-(4-chlorobenzyl)pyrrolidine (Compd. No. 1)

N-Benzoylglycine (9.3 mg, 0.055 mmol), 3-ethyl-1-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) (1.05 mg) and 1-hydroxybenzotriazole hydrate (HOBt) (7.4 mg) were added to a chloroform (2.5 mL) solution of 3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride (14.2 mg, 0.050 mmol) and triethylamine (15.2 mg). The resulting reaction mixture was stirred at 25° C. for 16 hours and then washed with a 2 M aqueous solution of NaOH (2 mL×2) and brine. After filtration through a PTFE membrane filter, the solvent was removed under reduced pressure to provide 3-(N-benzoylglycyl)amino-1-(4-chlorobenzyl)pyrrolidine (Compd. No. 1) as an off-white oil (17.7 mg, 95%). The purity was determined by RPLC/MS (95%). ESI/MS m/e 372.0 (M⁺+H, C₂₀H₂₂ClN₃O₂).

Examples 2 to 32

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method in Example 1. The data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 2.

TABLE 2 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%)  2 2 C₂₁H₂₄ClN₃O₂ 386 16.4 85  3 3 C₁₉H₂₁ClN₄O₂ 373 18.7 100   4 4 C₂₁H₂₁ClF₃N₃O₂ 440 57.2 69  5 82 C₂₂H₂₃ClF₃N₃O₂ 454 5.6 11  6 85 C₂₁H₂₄ClN₃O₂ 386 22.6 59  7 86 C₂₁H₂₃ClN₄O₄ 431 21.2 98  8 214 C₂₂H₂₅ClN₂O₂ 385 23.9 62  9 215 C₂₃H₂₇ClN₂O₃ 415 17.4 84 10 216 C₂₀H₂₃ClN₂O₂S 391 21.6 Q 11 217 C₂₃H₂₇ClN₂O₄ 431 15.3 66 12 218 C₂₃H₂₇ClN₂O₂ 399 12.8 64 13 219 C₂₂H₂₄ClFN₂O₃ 419 18.1 86 14 220 C₂₂H₂₅ClN₂O₂ 385 16.4 85 15 221 C₂₁H₂₃ClN₂O₂ 371 14.9 80 16 222 C₂₁H₂₂Cl₂N₂O₂ 405 13.3 65 17 223 C₂₅H₃₁ClN₂O₃ 443 18.4* 63 18 224 C₂₀H₂₃ClN₂O₃S 407 11.2 28 19 225 C₂₂H₂₆ClN₃O₂ 400 22.7 Q 20 226 C₂₃H₂₈ClN₃O₃ 430 21.0 98 21 227 C₂₂H₂₅Cl₂N₃O₂ 434 21.9 100  22 228 C₂₃H₂₈ClN₃O₃ 430 20.8 97 23 229 C₂₅H₃₂ClN₃O₂ 462 25.4 Q 24 230 C₂₆H₃₁ClFN₃O₂ 472 26.0 Q 25 231 C₂₄H₂₈ClN₃O₃ 442 30.3* Q 26 232 C₂₂H₃₂ClN₃O₂ 406 3.9 19 27 233 C₂₃H₂₈ClN₃O₂ 414 8.5 41 28 234 C₂₂H₂₇ClN₄O₂ 415 7.3 35 29 235 C₂₄H₂₉Cl₂N₃O₂ 462 9.0 39 30 236 C₂₅H₂₉ClN₄O₃S 501 17.4 69 31 237 C₂₁H₂₄ClN₃O₃ 402 14.2 71 32 238 C₂₁H₂₃Cl₂N₃O₃ 436 23.4 Q Notes: *indicates “yield (mg) of trifluoroacetate”. Q means “Quantitative”.

Reference Example 2 Synthesis of (R)-3-[(N-tert-butoxycarbonyl)glycyl]amino-1-(4 chlorobenzyl)pyrrolidine

A mixture of (R)-3-amino-1-(4-chlorobenzyl)pyrrolidine dihydrochloride (4.54 g, 16.0 mmol) with a 2 M solution (80 mL) of NaOH and ethyl acetate (80 mL) was stirred, and the organic layer was separated to extract the aqueous layer with ethyl acetate (80 mL×2). The organic layers were combined, dried over anhydrous sodium sulfate, then filtered and concentrated to thereby afford free (R)-3-amino-1-(4-chlorobenzyl)pyrrolidine (3.35 g, 99%).

To a dichloromethane (80 mL) solution of the (R)-3-amino-1-(4-chlorobenzyl)pyrrolidine (3.35 g, 16 mmol), were added triethylamine (2.5 mL, 17.6 mmol), N-tert-butoxycarbonylglycine (2.79 g, 16.0 mmol), EDCI (3.07 g, 16.0 mmol) and HOBt (12.16 g, 16 mmol). The resulting reaction mixture was stirred at 25° C. for 16 hours, and a 2 M solution (80 mL) of NaOH was then added thereto. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (100 mL×3). The organic layers were combined, washed with water (100 mL×2) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (SiO₂, ethyl acetate) to thereby provide the objective (R)-3-[N-(tert-butoxycarbonyl)glycyl]amino-1-(4-chlorobenzyl)pyrrolidine (5.40 g, 92%).

Reference Example 3 Synthesis of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine

A 4 M HCl dioxane (38 mL) solution was added to a methanol (60 mL) solution of (R)-3-[N-(tert-butoxycarbonyl)glycyl]amino-1-(4-chlorobenzyl)pyrrolidine (5.39 g, 14.7 mmol). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and a 2 M solution (80 mL) of NaOH was added. The mixture solution was extracted with dichloromethane (80 mL×3), and the extracts were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (SiO₂, ethyl acetate/ethanol/triethylamine=90:5:5) to afford (R)-3-(glycylamino)-1-(4-chlorobenzyl)pyrrolidine (3.374 g, 86%) ¹H NMR (CDCl₃, 270 MHz) δ 1.77 (dd, J=1.3 and 6.9 Hz, 1H), 2.20-3.39 (m, 2H), 2.53 (dd, J=3.3 and 9.6 Hz, 1H), 2.62 (dd, J=6.6 and 9.6 Hz, 1H), 2.78-2.87 (m, 1H), 3.31 (s, 2H), 3.57 (s, 2H), 4.38-4.53 (br, 1H), 7.18-7.32 (m, 4H), 7.39 (br, s, 1H).

Other 3-acylamino-1-(4-chlorobenzyl)pyrrolidines were synthesized by using the respective corresponding starting materials and reactants according to the methods of Reference Examples 2 and 3.

-   (S)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine: 3.45 g, 79% (two     steps). -   (R)-3-(β-alanylamino)-1-(4-chlorobenzyl)pyrrolidine: 3.79 g, 85%     (two steps). -   (S)-3-(β-alanylamino)-1-(4-chlorobenzyl)pyrrolidine: 3.72 g, 86%     (two steps) -   (R)-3-[(S)-alanylamino]-1-(4-chlorobenzyl)pyrrolidine: 368 mg, 65%     (two steps). -   (R)-3-[(R)-alanylamino]-1-(4-chlorobenzyl)pyrrolidine: 425 mg, 75%     (two steps). -   (R)-3-[(2S)-2-amino-3-thienylpropanoyl]amino-1-(4-chlorobenzyl)pyrrolidine: -   566 mg, 78% (two step). -   (R)-3-[(2R)-2-amino-3-thienylpropanoyl]amino-1-(4-chlorobenzyl)pyrrolidine:     5.85 mg, 81% (two steps). -   (R)-3-(2-amino-2-methylpropanoyl)amino-1-(4-chlorobenzyl)pyrrolidine:     404 mg, 66% (two steps). -   (R)-3-[(2S)-2-amino-4-(methylsulfonyl)butanoyl]amino-1-(4-chlorobenzyl)pyrrolidine:     535 mg, 72% (two steps).

Furthermore, (R)-3-(glycylamino)-1-(4-methylbenzyl)pyrrolidine, (R)-1-(4-bromobenzyl)-3-(glycylamino)pyrrolidine, (R)-1-(2,4-dimethylbenzyl)-3-(glycylamino)pyrrolidine and (R)-1-(3,5-dimethylisoxazol-4-ylmethyl)-3-(glycylamino)pyrrolidine were synthesized by using the respective corresponding starting materials and reactants according to the methods of Reference Examples 1, 2 and 3.

(R)-3-(glycylamino)-1-(4-methylbenzyl)pyrrolidine: 4.65 g, yield 62% (yield from 3-[(tert-butoxycarbonyl)amino]pyrrolidine).

(R)-1-(4-bromobenzyl)-3-(glycylamino)pyrrolidine: 2.55 g, yield 68% (yield from (R)-3-amino-1-(4-bromobenzyl)pyrrolidine); ¹H NMR (CDCl₃ 270 MHz) δ 1.37-1.78 (m, 3H), 2.23-2.39 (m, 2H), 2.50-2.67 (m, 2H), 2.80-2.89 (m, 1H), 3.32 (s, 2H), 3.58 (s, 2H), 4.39-4.55 (m, 1H), 7.21 (d, J=6.5 Hz, 2H), 7.45 (d, J=6.5 Hz, 2H).

(R)-1-(2,4-dimethylbenzyl)-3-(glycylamino)pyrrolidine: 1.56 g, yield 58% (yield from 3-[(tert-butroxycarbonyl)amino]pyrrolidine); ¹H NMR (CDCl₃, 270 MHz) δ 1.55-1.78 (m, 3H), 2.30 (s, 3H), 2.23-2.31 (m, 2H), 2.33 (s, 3H), 2.51-2.63 (m, 2H), 2.78-2.87 (m, 1H), 3.30 (s, 2H), 3.55 (s, 2H), 4.38-4.60 (m, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.97 (s, 1H), 7.13 (d, J=7.6 Hz, 1H), 7.43 (br-s, 1H).

(R)-1-(3,5-dimethylisoxazol-4-ylmethyl)-3-(glycylamino)pyrrolidine: 3.14 g, yield 45% (yield from 3-[(tert- butoxycarbonyl)amino]pyrrolidine).

Example 33 Synthesis of (S)-3-[N-[3,5-bis(trifluoromethyl)benzoyl]glycyl]amino-1-(4-chlorobenzyl)pyrrolidine (Compd. No. 5).

A chloroform solution (0.4 mL) of 3,5-bis(trifluoromethyl)benzoyl chloride (0.060 mmol) was added to a chloroform (1.0 mL) solution of (S)-1-(4-3-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol) and triethylamine (0.070 mmol). The resulting reaction mixture was stirred at room temperature for 2.5 hours, and an (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was then added. The prepared mixture was stirred at room temperature for 12 hours. The reaction mixture was filtered, and the resin was washed with dichloromethane (0.5 mL). The filtrate and the washing were combined, and dichloromethane (4 mL) was added. The resulting solution was washed with a 2 M aqueous solution (0.5 mL) of NaOH and concentrated to thereby provide (S)-3-[N-[3,5-bis(trifluoromethyl)benzoyl]glycyl]amino-1-(4-chlorobenzyl)pyrrolidine (Compd. No. 5) (14.4 mg, 57%). The purity was determined by RPLC/MS (97%). ESI/MS m/e 508.0 (M⁺+H, C₂₂H₂₀ClF₆N₃O₂).

Examples 34 to 239

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 33. Data of ESI/MS, yields (mg) and yields (%) are collectively shown on Table 3.

TABLE 3 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 34 5 C₂₂H₂₀ClF₆N₃O₂ 508.0 14.4 57 35 6 C₂₁H₂₁ClF₃N₃O₂ 440.0 17.0 77 36 7 C₂₀H₂₁BrClN₃O₂ 450.0 17.7 79 37 8 C₂₀H₂₁ClFN₃O₂ 390.0 12.7 65 38 9 C₂₀H₂₀Cl₃N₃O₂ 440.0 39.0 Q 39 10 C₂₁H₂₄ClN₃O₃ 402.5 23.5 Q 40 11 C₂₂H₂₆ClN₃O₄ 432.5 22.4 Q 41 12 C₂₂H₂₆ClN₃O₄ 432.5 15.9 74 42 13 C₂₁H₂₁ClF₃N₃O₂ 440.0 13.1 60 43 14 C₂₁H₂₄ClN₃O₂ 386.0 16.4 85 44 15 C₂₀H₂₁Cl₂N₃O₂ 406.0 15.7 77 45 16 C₂₁H₂₄ClN₃O₂ 402.0 28.2 Q 46 17 C₂₀H₂₀Cl₃N₃O₂ 442.0 35.6 Q 47 18 C₂₁H₂₁ClN₄O₂ 397.5 22.8 Q 48 19 C₂₁H₂₂ClN₃O₄ 416.0 16.3 78 49 20 C₂₁H₂₀ClF₄N₃O₂ 458.0 24.9 Q 50 21 C₂₁H₂₀ClF₄N₃O₂ 458.0 17.9 78 51 22 C₂₁H₂₀ClF₄N₃O₂ 458.0 9.4 41 52 23 C₂₁H₂₀ClF₄N₃O₂ 458.0 15.4 67 53 24 C₂₁H₂₁ClF₃N₃O₃ 456.0 20.7 91 54 25 C₂₁H₂₀ClF₄N₃O₂ 458.0 18.5 81 55 26 C₂₀H₂₁ClN₄O₄ 417.0 21.9 Q 56 27 C₂₀H₂₁ClN₄O₄ 417.0 16.8 81 57 28 C₂₀H₂₁ClN₄O₄ 417.0 6.8 33 58 29 C₂₂H₂₀ClF₆N₃O₂ 508.0 20.8 82 59 30 C₂₁H₂₁ClF₃N₃O₂ 440.0 15.2 69 60 31 C₂₀H₂₁BrClN₃O₂ 450.0 15.6 69 61 32 C₂₀H₂₁ClFN₃O₂ 390.0 11.8 61 62 33 C₂₀H₂₀Cl₃N₃O₂ 440.0 15.8 72 63 34 C₂₁H₂₄ClN₃O₃ 402.5 33.8 Q 64 35 C₂₂H₂₆ClN₃O₄ 432.5 56.1 Q 65 36 C₂₂H₂₆ClN₃O₄ 432.5 37.6 Q 66 37 C₂₁H₂₁ClF₃N₃O₂ 440.0 12.6 57 67 38 C₂₁H₂₄ClN₃O₂ 386.0 12.3 64 68 39 C₂₀H₂₁Cl₂N₃O₂ 406.0 15.9 78 69 40 C₂₁H₂₄ClN₃O₂ 402.0 11.6 58 70 41 C₂₀H₂₀Cl₃N₃O₂ 442.0 17.8 81 71 42 C₂₁H₂₁ClN₄O₂ 397.5 22.4 Q 72 43 C₂₁H₂₂ClN₃O₄ 416.0 30.1 Q 73 44 C₂₁H₂₀ClF₄N₃O₂ 458.0 13.4 59 74 45 C₂₁H₂₀ClF₄N₃O₂ 458.0 13.2 58 75 46 C₂₁H₂₀ClF₄N₃O₂ 458.0 14.4 63 76 47 C₂₁H₂₁ClF₃N₃O₃ 456.0 16.4 72 77 48 C₂₁H₂₀ClF₄N₃O₂ 458 16.5 72 78 49 C₂₀H₂₁ClN₄O₄ 417.0 12.5 60 79 50 C₂₁H₂₀ClF₄N₃O₂ 458.0 26.3 Q 80 51 C₂₀H₂₁BrClN₃O₂ 450.0 8.6 38 81 52 C₂₀H₂₁ClFN₃O₂ 390.5 4.1 21 82 53 C₂₀H₂₁Cl₂N₃O₂ 406.0 5.4 27 83 54 C₂₀H₂₀Cl₃N₃O₂ 440.0 8.8 40 84 55 C₂₀H₂₀BrCl₄N₃O₂ 440.0 7.7 35 85 56 C₂₁H₂₄ClN₃O₂ 386.0 4.8 25 86 57 C₂₂H₂₆ClN₃O₄ 429.5 4.9 23 87 58 C₂₀H₂₁Cl₂N₃O₂ 406.0 4.1 20 88 59 C₂₀H₂₁BrClN₃O₂ 452.0 3.5 16 89 60 C₂₆H₂₆ClN₃O₂ 448.5 7.3 33 90 61 C₂₁H₂₁ClF₃N₃O₂ 440.0 7.1 32 91 62 C₂₁H₂₄ClN₃O₂ 386.0 10.4 54 92 63 C₂₂H₂₆ClN₃O₂ 400.5 6.0 30 93 64 C₂₁H₂₁ClN₄O₂ 397.0 7.0 35 94 65 C₂₄H₂₄ClN₃O₂ 422.0 7.7 36 95 66 C₂₄H₂₄ClN₃O₂ 422.0 6.3 30 96 67 C₂₀H₂₀ClF₂N₃O₂ 408.0 4.7 23 97 68 C₂₀H₂₀ClF₂N₃O₂ 408.0 7.8 38 98 69 C₂₀H₂₀ClF₂N₃O₂ 408.0 7.3 36 99 70 C₂₀H₂₀ClF₂N₃O₂ 408.0 9.1 45 100 71 C₂₂H₂₆ClN₃O₄ 429.0 5.6 26 101 72 C₂₁H₂₁ClF₃N₃O₂ 456.0 6.2 27 102 73 C₂₁H₂₁ClF₃N₃O₂ 456.5 16.8 74 103 74 C₂₂H₂₄ClN₃O₄ 430.0 16.4 76 104 75 C₂₁H₂₀ClF₄N₃O₂ 458.0 16.1 70 105 76 C₂₁H₂₀ClF₄N₃O₂ 458.0 17.0 74 106 77 C₂₀H₁₉ClF₃N₃O₂ 426.0 16.2 76 107 78 C₂₀H₁₉ClF₃N₃O₂ 426.0 18.0 85 108 79 C₂₂H₂₀ClF₆N₃O₂ 508.0 18.8 74 109 80 C₂₂H₂₀ClF₆N₃O₂ 508.0 16.4 65 110 81 C₂₂H₂₆ClN₃O₂ 400.0 13.9 70 111 83 C₂₀H₂₁ClN₄O₄ 417.0 16.0 77 112 84 C₂₀H₂₁ClN₄O₄ 417.0 21.6 Q 113 87 C₂₃H₂₂ClF₆N₃O₂ 522.0 17.5 67 114 88 C₂₂H₂₃ClF₃N₃O₂ 454.0 13.9 61 115 89 C₂₁H₂₃BrClN₃O₂ 466.0 15.4 66 116 90 C₂₁H₂₃ClFN₃O₂ 404.0 10.7 53 117 91 C₂₁H₂₂Cl₃N₃O₂ 456.0 13.7 60 118 92 C₂₂H₂₆ClN₃O₃ 416.0 38.4 Q 119 93 C₂₃H₂₈ClN₃O₄ 446.0 25.2 Q 120 94 C₂₃H₂₈ClN₃O₄ 446.0 16.5 74 121 95 C₂₂H₂₃ClF₃N₃O₂ 454.0 16.3 72 122 96 C₂₂H₂₆ClN₃O₂ 400.5 16.7 84 123 97 C₂₁H₂₃Cl₂N₃O₂ 420.0 11.2 53 124 98 C₂₂H₂₆ClN₃O₂ 416.5 11.8 57 125 99 C₂₁H₂₂Cl₃N₃O₂ 454.0 14.8 65 126 100 C₂₂H₂₃ClN₄O₂ 411.0 9.5 46 127 101 C₂₂H₂₄ClN₃O₄ 430.5 13.2 61 128 102 C₂₂H₂₂ClF₄N₃O₂ 472.0 13.1 56 129 103 C₂₂H₂₂ClF₄N₃O₂ 472.0 36.5 Q 130 104 C₂₂H₂₂ClF₄N₃O₂ 472.0 22.8 97 131 105 C₂₂H₂₂ClF₄N₃O₂ 472.0 20.1 85 132 106 C₂₂H₂₃ClF₃N₃O₃ 470.0 27.4 Q 133 107 C₂₂H₂₂ClF₄N₃O₂ 472.0 18.5 78 134 108 C₂₁H₂₃ClN₄O₄ 431.0 11.9 55 135 109 C₂₁H₂₃ClN₄O₄ 431.0 23.9 Q 136 110 C₂₁H₂₃ClN₄O₄ 431.0 24.4 Q 137 111 C₂₃H₂₂ClF₆N₃O₂ 522.0 9.5 36 138 112 C₂₂H₂₃ClF₃N₃O₂ 454.0 3.9 17 139 113 C₂₁H₂₃BrClN₃O₂ 466.0 7.5 32 140 114 C₂₁H₂₃ClFN₃O₂ 404.0 6.1 30 141 115 C₂₁H₂₂Cl₃N₃O₂ 456.0 6.6 29 142 116 C₂₂H₂₆ClN₃O₃ 416.0 4.8 23 143 117 C₂₃H₂₈ClN₃O₄ 446.0 6.4 29 144 118 C₂₃H₂₈ClN₃O₄ 446.0 24.6 Q 145 119 C₂₂H₂₃ClF₃N₃O₂ 454.0 5.2 23 146 120 C₂₂H₂₆ClN₃O₂ 400.5 4.4 22 147 121 C₂₁H₂₃Cl₂N₃O₂ 420.0 7.8 37 148 122 C₂₂H₂₆ClN₃O₂ 416.5 14.1 68 149 123 C₂₁H₂₂Cl₃N₃O₂ 454.0 5.4 24 150 124 C₂₂H₂₃ClN₄O₂ 411.0 34.0 Q 151 125 C₂₂H₂₄ClN₃O₄ 430.5 32.0 Q 152 126 C₂₂H₂₂ClF₄N₃O₂ 472.0 4.6 19 153 127 C₂₂H₂₂ClF₄N₃O₂ 472.0 10.4 44 154 128 C₂₂H₂₂ClF₄N₃O₂ 472.0 7.3 31 155 129 C₂₂H₂₂ClF₄N₃O₂ 472.0 13.5 57 156 130 C₂₂H₂₃ClF₃N₃O₃ 470.0 15.1 64 157 131 C₂₂H₂₂ClF₄N₃O₂ 472.0 8.6 36 158 132 C₂₁H₂₃ClN₄O₄ 431.0 4.4 20 159 133 C₂₁H₂₃ClN₄O₄ 431.0 32.0 Q 160 134 C₂₁H₂₃ClN₄O₄ 431.0 6.9 32 161 135 C₂₁H₂₃BrClN₃O₂ 466.0 7.8 34 162 136 C₂₁H₂₃ClFN₃O₂ 404.0 13.7 68 163 137 C₂₁H₂₃Cl₂N₃O₂ 420.5 14.6 69 164 138 C₂₁H₂₂Cl₃N₃O₂ 454.0 17.7 78 165 139 C₂₁H₂₂BrCl₄N₃O₂ 454.0 17.2 76 166 140 C₂₂H₂₆ClN₃O₂ 400.0 15.0 75 167 141 C₂₃H₂₈ClN₃O₄ 443.5 13.9 62 168 142 C₂₁H₂₃Cl₂N₃O₂ 420.0 13.7 65 169 143 C₂₁H₂₃BrClN₃O₂ 464.0 16.1 69 170 144 C₂₇H₂₈ClN₃O₂ 462.0 17.6 76 171 145 C₂₂H₂₃ClF₃N₃O₂ 454.0 16.0 71 172 146 C₂₂H₂₆ClN₃O₂ 400.0 14.9 75 173 147 C₂₃H₂₈ClN₃O₂ 414.0 16.2 78 174 148 C₂₂H₂₃ClN₄O₂ 411.0 14.9 73 175 149 C₂₅H₂₆ClN₃O₂ 436.0 17.1 78 176 150 C₂₅H₂₆ClN₃O₂ 436.0 13.1 60 177 151 C₂₁H₂₂ClF₂N₃O₂ 422.0 14.8 70 178 152 C₂₁H₂₂ClF₂N₃O₂ 422.0 15.3 73 179 153 C₂₁H₂₂ClF₂N₃O₂ 422.0 15.3 73 180 154 C₂₁H₂₂ClF₂N₃O₂ 422.0 16.4 78 181 155 C₂₃H₂₈ClN₃O₄ 443.0 16.9 76 182 156 C₂₂H₂₃ClF₃N₃O₂ 470.5 12.6 54 183 157 C₂₂H₂₃ClF₃N₃O₂ 470.0 20.0 85 184 158 C₂₃H₂₆ClN₃O₄ 444.0 17.4 78 185 159 C₂₂H₂₂ClF₄N₃O₂ 472.0 18.4 78 186 160 C₂₂H₂₂ClF₄N₃O₂ 472.0 19.6 83 187 161 C₂₁H₂₁ClF₃N₃O₂ 440.0 17.0 77 188 162 C₂₁H₂₁ClF₃N₃O₂ 440.0 17.1 78 189 163 C₂₃H₂₂ClF₆N₃O₂ 522.0 20.8 80 190 164 C₂₃H₂₂ClF₆N₃O₂ 522.0 2.7 10 191 165 C₂₃H₂₈ClN₃O₂ 414.0 16.4 79 192 166 C₂₂H₂₃ClF₃N₃O₂ 454.0 8.6 38 193 167 C₂₁H₂₃BrClN₃O₂ 464.0 11.6 50 194 168 C₂₁H₂₃Cl₂N₃O₂ 420.0 11.5 55 195 169 C₂₁H₂₂Cl₃N₃O₂ 454.0 10.0 44 196 170 C₂₂H₂₂ClF₄N₃O₂ 472.0 10.4 44 197 171 C₂₁H₂₃Cl₂N₃O₂ 420.0 8.9 42 198 172 C₂₁H₂₄ClN₃O₂ 386.0 10.3 53 199 173 C₂₁H₂₃ClN₄O₄ 431.0 14.6 68 200 174 C₂₂H₂₃ClF₃N₃O₂ 454.0 10.4 46 201 175 C₂₁H₂₃BrClN₃O₂ 464.0 13.4 58 202 176 C₂₁H₂₃Cl₂N₃O₂ 420.0 12.7 60 203 177 C₂₁H₂₂Cl₃N₃O₂ 454.0 13.2 58 204 178 C₂₂H₂₂ClF₄N₃O₂ 472.0 12.9 55 205 179 C₂₁H₂₃Cl₂N₃O₂ 420.0 13.3 63 206 180 C₂₁H₂₄ClN₃O₂ 386.0 24.2 Q 207 181 C₂₁H₂₃ClN₄O₄ 431.0 1.0  1 208 182 C₂₃H₂₅ClF₃N₃O₂ 468.0 15.1 65 209 183 C₂₂H₂₅BrClN₃O₂ 478.0 18.0 75 210 184 C₂₂H₂₅Cl₂N₃O₂ 434.0 16.3 75 211 185 C₂₂H₂₄Cl₃N₃O₂ 468.0 18.6 79 212 186 C₂₃H₂₄ClF₄N₃O₂ 486.0 16.5 68 213 187 C₂₂H₂₅Cl₂N₃O₂ 434.0 14.4 66 214 188 C₂₂H₂₆ClN₃O₂ 400.0 14.0 70 215 189 C₂₂H₂₅ClN₄O₄ 445.0 16.8 76 216 190 C₂₆H₂₅ClF₃N₃O₂S 536.0 17.7 66 217 191 C₂₆H₂₅BrClN₃O₂S 546.0 20.4 75 218 192 C₂₅H₂₅Cl₂N₃O₂S 502.0 16.9 67 219 193 C₂₅H₂₄Cl₃N₃O₂S 536.0 18.3 68 220 194 C₂₆H₂₄ClF₄N₃O₂S 554.0 19.4 70 221 195 C₂₅H₂₅Cl₂N₃O₂S 502.0 19.1 76 222 196 C₂₅H₂₆ClN₃O₂S 468.0 16.0 68 223 197 C₂₅H₂₅ClN₄O₄S 513.0 18.4 72 224 198 C₂₆H₂₅ClF₃N₃O₂S 536.0 13.9 52 225 199 C₂₅H₂₅BrClN₃O₂S 546.0 12.9 47 226 200 C₂₅H₂₅Cl₂N₃O₂S 502.0 15.6 62 227 201 C₂₅H₂₄Cl₃N₃O₂S 536.0 17.3 64 228 202 C₂₆H₂₄ClF₄N₃O₂S 554.0 15.4 56 229 203 C₂₅H₂₅Cl₂N₃O₂S 502.0 13.5 54 230 204 C₂₅H₂₆ClN₃O₂S 468.0 13.7 59 231 205 C₂₅H₂₅ClN₄O₄S 513.0 13.9 54 232 206 C₂₄H₂₇ClF₃N₃O₄S 546.0 10.0 37 233 207 C₂₃H₂₇BrClN₃O₄S 558.0 17.1 61 234 208 C₂₃H₂₇Cl₂N₃O₄S 512.0 17.0 66 235 209 C₂₃H₂₆Cl₃N₃O₄S 546.0 7.3 27 236 210 C₂₄H₂₆ClF₄N₃O₄S 564.0 19.2 68 237 211 C₂₃H₂₇Cl₂N₃O₄S 512.0 7.9 31 238 212 C₂₃H₂₈ClN₃O₄S 478.0 13.7 57 239 213 C₂₃H₂₇ClN₄O₄S 523.0 5.5 21 Note: Q means “Quantitative”.

Example 240 Synthesis of (R)-3-[N-[3-fluoro-5-(trifluoromethyl)benzoyl]glycyl]amino-1-(3,5-dimethylisoxazol-4-ylmethyl)-pyrrolidine (Compd. No. 1191)

A dichloromethane solution (1 mL) of 3-fluoro-5-(trifluoromethyl)benzoyl chloride (0.058 mmol) was added to a solution of (R)-1-(3,5-dimethylisoxazol-4-ylmethyl)-3-(glycylamino)pyrrolidine (0.050 mmol) and a piperidinomethylpolystyrene (58 mg) in chloroform (0.2 mL) and dichloromethane (0.75 ml). The reaction mixture was stirred at room temperature for 2 hours, and methanol (1.0 mL) was then added. The resulting mixture was stirred at room temperature for 10 hours. The reaction mixture was loaded onto a Varian™ SCX column and washed with methanol (16 mL). The obtained crude product was eluted with a solution of 2 M NH₃ in methanol (6 mL) and concentrated to provide (R)-3-[N-[3-fluoro-5-(trifluoromethyl)benzoyl]glycyl]amino-1-(3,5-dimethylisoxazol-4-ylmethyl)pyrrolidine (Compd. No. 1191) (19.5 mg, 88%). The purity was determined by RPLC/MS (100%). ESI/MS m/e 443.2 (M⁺+H, C₂₀H₂₂F₄N₄O₃).

Examples 241 to 265

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 240. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 4.

TABLE 4 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 241 1192 C₂₀H₂₂F₄N₄O₃ 443.2 19.2 87 242 1193 C₂₀H₂₃F₃N₄O₄ 441.0 17.5 79 243 1194 C₂₁H₂₂F₆N₄O₃ 493.0 20.4 83 244 1195 C₁₉H₂₃BrN₄O₃ 435.1 16.8 77 245 1196 C₁₉H₂₃N₅O₅ 402.2 16.2 81 246 1197 C₂₀H₂₂F₄N₄O₃ 443.2 17.6 80 247 1198 C₁₉H₂₃ClN₄O₃ 391.0 16.5 84 248 1199 C₂₀H₂₆N₄O₃ 371.0 16.1 87 249 1200 C₁₉H₂₂Cl₂N₄O₃ 425.0 18.0 85 250 1201 C₁₉H₂₂F₂N₄O₃ 393.0 16.6 85 251 1202 C₂₀H₂₂F₄N₄O₃ 443.2 16.8 76 252 1203 C₂₂H₂₄F₃N₃O₃ 436.2 17.1 79 253 1204 C₂₃H₂₃F₆N₃O₂ 488.2 18.1 74 254 1205 C₂₁H₂₄BrN₃O₂ 430.0 17.5 81 255 1206 C₂₁H₂₄N₄O₄ 397.0 16.2 82 256 1207 C₂₂H₂₃F₄N₃O₂ 438.2 17.5 80 257 1208 C₂₁H₂₄ClN₃O₂ 386.0 15.8 82 258 1209 C₂₂H₂₇N₃O₂ 366.0 15.7 86 259 1210 C₂₁H₂₃Cl₂N₃O₂ 420.0 17.8 85 260 1211 C₂₁H₂₃F₂N₃O₂ 388.0 16.3 84 261 1212 C₂₂H₂₃F₄N₃O₂ 438.2 17.4 80 262 1213 C₂₄H₂₄ClF₆N₃O₂ 536.2 24.0 90 263 1214 C₂₃H₂₄ClF₄N₃O₃ 486.2 22.2 91 264 1215 C₂₂H₂₄Cl₃N₃O₂ 467.9 20.9 89 265 1216 C₂₂H₂₄ClF₂N₃O₂ 436.0 19.3 89

Example 266 Synthesis of (R)-1-(4-chlorobenzyl)-3-[[N-(4-dimethylaminobenzoyl)glycyl]amino]pyrrolidine (Compd. No. 952)

Triethylamine (0.021 mL, 0.15 mmol), 4-(dimethylamino)benzoic acid (10 mg, 0.061 mmol), EDCI (10.2 mg, 0.053 mmol) and HOBt (7.5 mg, 0.055 mmol) were added to a chloroform (2 mL) solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (13.8 mg, 0.052 mmol). The resulting reaction mixture was stirred at room temperature for 15 hours. The solution was washed with a 2 M aqueous solution of NaOH (2 mL×2) and brine (2 mL), filtered through a PTFE membrane by using dichloromethane (3 mL), dried and concentrated to thereby afford (R)-1-(4-chlorobenzyl)-3-[[N-(4-dimethylaminobenzoyl)glycyl]amino]pyrrolidine (Compd. No. 952) (24.9 mg). The purity was determined by RPLC/MS (91%). ESI/MS m/e 415.0 (M⁺+H, C₂₂H₂₇ClN₄O₂).

Examples 267 to 347

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 266. The obtained products, if necessary, were purified by solid-phase extraction (Varian™ SCX column) or chromatography (HPLC-C₁₈) to provide the objective compounds. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 5.

TABLE 5 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 267 951 C₂₂H₂₄ClN₃O₄ 430.0 26.3 Q 268 953 C₂₃H₂₉ClN₄O₂ 429.0 28.8 Q 269 954 C₂₁H₂₅ClN₄O₂ 401.0 27.9 Q 270 955 C₂₂H₂₇ClN₄O₂ 415.0 26.8 Q 271 956 C₂₁H₂₄ClN₃O₃ 402.0 10.3 51 272 957 C₂₀H₂₂ClN₃O₃ 388.0 1.4  7 273 958 C₂₁H₂₄ClN₃O₃ 402.5 1.2  6 274 959 C₂₂H₂₅ClN₄O₃ 429.5 4.7 22 275 960 C₂₃H₂₇ClN₄O₃ 443.0 10.9 49 276 961 C₂₁H₂₅ClN₄O₂ 401.0 28.4 Q 277 962 C₂₂H₂₇ClN₄O₂ 415.0 24.9 Q 278 963 C₂₁H₂₄ClN₃O₃ 402.0 4.4 22 279 964 C₂₂H₂₄ClN₃O₄ 430.0 29.5 Q 280 965 C₂₃H₂₆ClN₃O₄ 444.0 27.2 Q 281 966 C₂₂H₂₄ClN₃O₃ 414.0 27.0 Q 282 967 C₂₃H₂₆ClN₃O₃ 428.0 27.0 Q 283 968 C₂₂H₂₃ClN₄O₂ 411.0 21.4 Q 284 969 C₂₃H₂₅ClN₄O₂ 425.0 27.6 Q 285 970 C₂₂H₂₇ClN₄O₂ 415.0 28.6 Q 286 971 C₂₃H₂₉ClN₄O₂ 429.0 27.9 Q 287 972 C₂₀H₂₃ClN₄O₂ 387.0 26.2 Q 288 973 C₂₁H₂₅ClN₄O₂ 401.0 26.8 Q 289 974 C₂₀H₂₃ClN₄O₂ 387.0 26.6 Q 290 975 C₂₁H₂₅ClN₄O₂ 401.0 28.2 Q 291 976 C₂₂H₂₃ClN₄O₂ 411.0 29.2 Q 292 977 C₂₃H₂₅ClN₄O₂ 425.0 29.5 Q 293 978 C₂₀H₂₁ClN₆O₂ 413.0 2.2 11 294 979 C₂₁H₂₃ClN₆O₂ 427.0 10.2 48 295 980 C₂₂H₂₅ClN₄O₃ 429.0 28.8 Q 296 981 C₂₃H₂₇ClN₄O₃ 443.0 11.9 54 297 982 C₂₂H₂₇ClN₄O₂ 415.0 27.4 Q 298 983 C₂₃H₂₉ClN₄O₂ 429.5 28.1 Q 299 984 C₂₁H₂₄ClN₃O₃ 402.0 27.7 Q 300 985 C₂₂H₂₆ClN₃O₃ 416.0 28.6 Q 301 1149 C₂₁H₂₈N₄O₄ 401 15.5* 38 302 1150 C₂₁H₂₈N₄O₃ 385 10.9* 28 303 1151 C₂₁H₂₅F₃N₄O₃ 439 17.3* 39 304 1152 C₂₁H₂₄FN₅O₃ 415 12.7* 30 305 1153 C₂₁H₂₄ClN₅O₃ 430 17.5* 41 306 1154 C₂₂H₂₇N₅O₃ 410 20.6* 50 307 1155 C₁₉H₂₃F₃N₄O₄ 429 13.8* 32 308 1156 C₂₁H₃₀N₄O₄ 403 17.7* 43 309 1157 C₁₈H₂₄N₄O₃S₂ 409 12.6* 30 310 1158 C₁₉H₂₃Cl₂N₅O₃ 440 16.9* 38 311 1159 C₂₂H₃₁N₅O₆ 462 38.6* 85 312 1160 C₂₀H₂₆BrN₅O₃ 464 20.4 45 313 1289 C₂₀H₂₇N₅O₄ 403 5.8* 14 314 1290 C₂₁H₂₉N₅O₃ 400 6.9* 17 315 1291 C₂₄H₂₈N₄O₂ 405 22.4 68 316 1292 C₂₂H₂₇BrN₄O₂ 461 23.8 15 317 1293 C₂₂H₂₃F₄N₃O₂ 438 20.9 59 318 1294 C₂₂H₂₃F₄N₃O₂ 438 20.8 59 319 1295 C₂₃H₃₁N₃O₃ 398 17.5 54 320 1296 C₂₀H₂₅N₃O₂S₂ 404 18.8 58 321 1297 C₂₁H₂₄F₃N₃O₃ 424 18.1 53 322 1388 C₂₁H₃₂N₆O₃ 417 7.4* 24 323 1389 C₁₉H₂₂N₆O₄ 399 15.2 48 324 1401 C₂₃H₂₅ClN₄O₂ 425 8.3* 16 325 1402 C₂₄H₃₂N₄O₅ 457 8.3* 15 326 1403 C₂₀H₂₄N₄O₂ 353 14.8 52 327 1404 C₂₀H₂₄N₄O₂ 353 17.0 60 328 1405 C₂₁H₂₆N₄O₂S 399 17.3 54 329 1407 C₂₂H₂₈N₄O₂S 413 19.1 57 330 1410 C₁₉H₂₄N₄O₃ 357 9.7* 59 331 1769 C₂₂H₂₆ClF₃N₄O₅ 519 11.6* 20 332 1770 C₂₆H₂₈Cl₂N₆O₄ 559 13.1* 21 333 1771 C₂₆H₃₇N₅O₄ 484 12.7* 23 334 1772 C₂₈H₃₉N₅O₄ 510 5.5*  9 335 1773 C₂₈H₃₇N₅O₄ 509 6.2* 11 336 1774 C₂₈H₃₄N₆O₆ 551 13.6* 22 337 2039 C₁₉H₂₄N₄O₂ 341 5.2* 14 338 2040 C₂₂H₂₇N₃O₄ 398 2.0*  5 339 2041 C₂₃H₂₉N₃O₃ 396 6.2* 15 340 2042 C₂₅H₃₇N₃O₂ 413 2.6*  6 341 2043 C₂₄H₃₁N₃O₂ 394 6.8* 17 342 2044 C₂₅H₂₈N₄O₄ 449 8.7* 16 343 2045 C₂₆H₂₉ClN₆O₄ 525 11.4* 19 344 2046 C₂₇H₃₂N₆O₄ 505 7.7* 13 345 2047 C₂₈H₃₂N₄O₄ 489 10.0* 18 346 2048 C₂₈H₃₇N₅O₅ 524 3.7*  6 347 2049 C₂₈H₃₇N₅O₄ 509 5.3*  9 Note: *indicated “yield (mg) of trifluoroacetate”. Q means “Quantitative”.

Example 348 Synthesis of (R)-1-(4-chlorobenzyl)-3-[[N-(2-amino-5-chlorobenzoyl)glycyl]amino]pyrrolidine (Compd. No. 1084)

2-Amino-5-chlorobenzoic acid (0.060 mL) and diisopropylcarbodiimide (0.060 mol) were added to a chloroform (2 mL) solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol). The resulting reaction solution was stirred at room temperature for 15 hours. The mixture solution was loaded onto a Varian™ SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a solution of 2 M NH₃ in methanol (5 mL) and concentrated to thereby afford (R)-1-(4-chlorobenzyl)-3-[N-[2-amino-5-chlorobenzoyl]glycyl]amino]pyrrolidine (Compd. No. 1084) (12.7 mg, 60%). The purity was determined by RPLC/MS (87%). ESI/MS m/e 421.0 (M⁺+H, C₂₀H₂₂Cl₂N₄O₂).

Examples 349 to 361

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 348. When the starting amine remained, a chloroform (1 mL) solution of an isocyanatomethylated polystyrene (50 mg) was added and reacted at room temperature. The resulting reaction mixtures were filtered and concentrated to thereby afford the objective compounds. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 6.

TABLE 6 Molecular ESI/MS Yield Example Compd. No. Formula m/e (mg) Yield (%) 349 1085 C₂₀H₂₂ClN₈O₄ 432.0 4.1 19 350 1086 C₂₀H₂₃ClN₄O₂ 387.0 7.9 41 351 1087 C₂₂H₂₃ClN₄O₂ 411.0 15.0 73 352 1088 C₁₈H₂₀ClN₃O₃ 362.0 12.9 71 353 1089 C₂₂H₂₂ClFN₄O₂ 429.0 16.0 75 354 1090 C₂₂H₂₆ClN₃O₃ 416.0 15.8 76 355 1091 C₂₁H₂₄Cl₂N₄O₂ 435.0 10.9 50 356 1092 C₂₁H₂₄ClN₅O₄ 446.0 7.9 35 357 1093 C₂₁H₂₅ClN₄O₂ 401.0 9.5 47 358 1094 C₂₃H₂₅ClN₄O₂ 425.0 15.8 74 359 1095 C₁₉H₂₂ClN₃O₃ 376.0 13.5 72 360 1096 C₂₃H₂₄ClFN₄O₂ 443.0 11.8 53 361 1097 C₂₃H₂₈ClN₃O₃ 430.0 15.1 70

Example 362 Synthesis of (R)-1-(4-chlorobenzyl-3-[[N-(3-bromo-4-methylbenzoyl)glycyl]amino]pyrrolidine (Compd. No. 1098)

3-Brmo-4-methylbenzoic acid (0.060 mL), diisopropylcarbodiimide (0.060 mmol) and HOBt (0.060 mmol) were added to a solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol) in chloroform (1.35 mL) and tert-butanol (0.15 mL). The resulting reaction mixture was stirred at room temperature for 15 hours. The mixture solution was loaded onto a Varian™ SCX column and washed with methanol/chloroform=1:1 (12 mL) and methanol (12 mL). The crude product was eluted with a solution of 2 M NH₃ in methanol (5 mL) and concentrated to thereby provide (R)-1-(4-chlorobenzyl)-3-[[N-(3-bromo-4-methylbenzoyl)glycyl]amino]pyrrolidine (Compd. No. 1098) (11.6 mg, 50%). The purity was determined by RPLC/MS (94%). ESI/MS m/e 466.0 (M⁺+H, C₂₁H₂₃BrClN₃O₂).

Examples 363 to 572

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 362. The obtained products, if necessary, were purified by preparative TLC to afford the objective compounds. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 7.

The following three compounds were obtained as by-products of the Compd. Nos. 1415, 1416 and 1417.

Compd. No. 1419: 7.9 mg, yield 38%, ESI/MS m/e 419.0 (C₂₀H₂₃ClN₄O₂S).

Compd. No. 1420: 7.1 mg, yield 36%, ESI/MS m/e 399.2 (C₂₃H₂₆N₄O₂S).

Compd. No. 1421: 7.4 mg, yield 37%, ESI/MS m/e 404.2 (C₁₉H₂₅N₅O₃S).

TABLE 7 ESI/MS Yield Yield Example Compd. No. Molecular Formula m/e (mg) (%) 363 1099 C₂₀H₂₀BrClFN₃O₂ 470.0 3.1 13 364 1100 C₂₀H₂₀Cl₂FN₃O₂ 424.0 3.1 15 365 1101 C₂₁H₂₃ClIN₃O₂ 512.0 12.5 49 366 1102 C₂₁H₂₃ClN₄O₄ 431.2 7.7 36 367 1103 C₂₂H₂₆BrN₃O₂ 446.0 13.8 62 368 1104 C₂₁H₂₃BrFN₃O₂ 450.0 16.5 74 369 1105 C₂₁H₂₃ClFN₃O₂ 404.2 14.7 73 370 1106 C₂₂H₂₆IN₃O₂ 492.0 18.5 75 371 1107 C₂₂H₂₆N₄O4 411.2 15.2 74 372 1108 C₂₀H₂₅BrN₄O₃ 449.0 12.8 57 373 1109 C₁₉H₂₂BrFN₄O₃ 455.0 16.2 71 374 1110 C₁₉H₂₂ClFN₄O₃ 409.2 14.4 70 375 1111 C₂₀H₂₅IN₄O₃ 497.0 17.9 72 376 1112 C₂₀H₂₅N₅O₅ 416.2 14.9 72 377 1113 C₂₃H₂₇BrClN₃O₂ 494.0 16.1 65 378 1114 C₂₂H₂₄BrClFN₃O₂ 498.0 20.2 81 379 1115 C₂₂H₂₄Cl₂FN₃O₂ 452.2 18.6 82 380 1116 C₂₃H₂₇ClIN₃O₂ 539.1 21.9 81 381 1117 C₂₃H₂₇ClN₄O₄ 459.2 18.7 81 382 1171 C₂₁H₂₃BrClN₃O₂ 466.0 4.9 21 383 1172 C₂₂H₂₃ClN₄O₃ 427.2 16.1 75 384 1173 C₂₃H₂₅ClN₄O₃ 441.2 22.8 Q 385 1174 C_(2O)H₂₂ClFN₄O₂ 405.2 21.4 Q 386 1175 C₂₂H₂₆BrN₃O₂ 446.0 15.8 71 387 1176 C₂₃H₂₆N₄O₃ 407.2 17.6 87 388 1177 C₂₄H₂₈N₄O₃ 421.2 20.2 96 389 1178 C₂₁H₂₅FN₄O₂ 385.0 16.2 84 390 1179 C₂₁H₂₅N₅O₄ 412.2 2.3 11 391 1180 C₂₃H₂₆N₄O₂ 391.0 21.6 Q 392 1181 C₂₀H₂₅BrN₄O₃ 451.0 20.1 89 393 1182 C₂₁H₂₅N₅O₄ 412.2 13.3 65 394 1183 C₂₂H₂₇N₅O₄ 426.2 20.9 98 395 1184 C₁₉H₂₄FN₅O₃ 390.0 20.0 Q 396 1185 C₁₉H₂₄N₆O₅ 417.2 18.2 87 397 1186 C₂₁H₂₅N₅O₃ 396.2 17.6 89 398 1187 C₂₃H₂₇BrClN₃O₂ 494.0 22.1 90 399 1188 C₂₄H₂₇ClN₄O₃ 455.2 17.2 76 400 1189 C₂₅H₂₉ClN₄O₃ 469.2 21.1 90 401 1190 C₂₂H₂₆ClFN₄O₂ 433.2 20.4 94 402 1217 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 38.5 81 403 1218 C₂₁H₂₃ClFN₃O₂ 404.2 35.6 88 404 1219 C₂₁H₂₃Cl₂N₃O₂ 420.0 3.7  9 405 1220 C₂₀H₂₂ClIN₄O₂ 513.0 53.0 Q 406 1221 C₂₀H₂₁ClF₂N₄O₂ 423.0 38.7 92 407 1222 C₁₉H₂₃ClN₄O₂ 375.2 33.6 90 408 1223 C₂₆H₂₆ClN₃O₂S 496.0 43.7 88 409 1224 C₂₀H₂₁ClN₄O₅ 433.0 40.6 94 410 1225 C₂₂H₂₃ClF₃N₃O₂ 454.2 18.4 41 411 1226 C₂₂H₂₆FN₃O₂ 384.0 17.1 45 412 1227 C₂₂H₂₆ClN₃O₂ 400.2 17.5 44 413 1228 C₂₁H₂₅IN₄O₂ 493.0 23.3 47 414 1229 C₂₁H₂₄F₂N₄O₂ 403.2 18.4 46 415 1230 C₂₀H₂₆N₄O₂ 355.2 15.7 44 416 1231 C₂₇H₂₉N₃O₂S 476.0 20.9 88 417 1232 C₂₁H₂₄N₄O₅ 413.0 19.9 96 418 1233 C₂₀H₂₂ClF₃N₄O₃ 459.0 19.4 85 419 1234 C₂₀H₂₅FN₄O₃ 389.0 17.8 92 420 1235 C₂₀H₂₅ClN₄O₃ 405.2 18.7 92 421 1236 C₁₉H₂₄IN₅O₃ 498.0 23.9 96 422 1237 C₁₉H₂₃F₂N₅O₃ 408.2 19.0 93 423 1238 C₁₈H₂₅N₅O₃ 360.0 16.3 91 424 1239 C₂₅H₂₈N₄O₃S 481.2 21.4 89 425 1240 C₁₉H₂₃N₅O₆ 418.0 19.9 95 426 1241 C₂₃H₂₄Cl₂F₃N₃O₂ 502.0 22.5 90 427 1242 C₂₃H₂₇ClFN₃O₂ 432.2 21.2 98 428 1243 C₂₃H₂₇Cl₂N₃O₂ 448.0 21.6 96 429 1244 C₂₂H₂₆ClIN₄O₂ 541.0 26.4 98 430 1245 C₂₂H₂₅ClF₂N₄O₂ 451.0 21.3 94 431 1246 C₂₁H₂₇ClN₄O₂ 403.2 19.4 96 432 1247 C₂₈H₃₀ClN₃O₂S 524.0 24.7 94 433 1248 C₂₂H₂₅ClN₄O₅ 461.0 20.7 90 434 1249 C₂₀H₂₀Cl₂N₄O₄ 451.0 7.4 33 435 1250 C₂₁H₂₃ClN₄O₄ 431.2 15.5 72 436 1251 C₁₉H₂₂ClN₅O₅ 436.0 22.9 Q 437 1252 C₂₃H₂₈ClN₃O₂ 414.2 17.9 86 438 1253 C₂₄H₃₁N₃O₂ 394.2 15.8 80 439 1254 C₂₂H₃₀N₄O₃ 399.2 17.3 87 440 1255 C₂₀H₂₂BrClN₄O₂ 467.0 21.3 91 441 1256 C₂₁H₂₅BrN₄O₂ 445.0 20.7 93 442 1257 C₁₉H₂₄BrN₅O₃ 450.0 21.8 97 443 1258 C₂₁H₂₅ClN₄O₂ 401.2 18.1 90 444 1259 C₁₉H₂₄ClN₅O₃ 406.0 20.1 99 445 1260 C₂₃H₂₉N₃O₃ 396.2 16.8 85 446 1261 C₂₃H₃₀ClN₃O₃ 432.2 19.8 92 447 1262 C₂₄H₃₃N₃O₃ 412.2 17.4 85 448 1263 C₂₂H₃₂N₄O₄ 417.2 18.7 90 449 1264 C₂₅H₂₆ClN₃O₃ 452.2 29.1 Q 450 1265 C₂₆H₂₉N₃O₃ 432.2 18.1 84 451 1266 C₂₄H₂₈N₄O₄ 437.2 19.3 88 452 1267 C₂₃H₂₂ClF₃N₄O₃ 495.2 20.6 83 453 1268 C₂₁H₂₃Cl₂N₃O₃ 436.0 17.5 80 454 1269 C₂₀H₂₁BrClN₃O₃ 468.0 19.2 82 455 1270 C₂₀H₂₁Cl₂N₃O₃ 422.2 17.3 82 456 1271 C₂₀H₂₀ClFN₄O₄ 435.0 17.1 79 457 1272 C₂₄H₂₅F₃N₄O₃ 475.2 21.7 91 458 1273 C₂₂H₂₆ClN₃O₃ 416.2 17.8 86 459 1274 C₂₁H₂₄BrN₃O₃ 448.0 19.5 87 460 1275 C₂₁H₂₄ClN₃O₃ 402.2 16.7 83 461 1276 C₂₁H₂₃FN₄O₄ 415.2 18.1 87 462 1277 C₂₂H₂₄F₃N₅O₄ 480.2 20.3 85 463 1278 C₂₀H₂₅ClN₄O₄ 421.2 18.6 88 464 1279 C₁₉H₂₃BrN₄O₄ 451.0 21.3 94 465 1280 C₁₉H₂₃ClN₄O₄ 407.2 19.1 94 466 1281 C₁₉H₂₂FN₅O₅ 420.2 19.1 91 467 1282 C₂₅H₂₆ClF₃N₄O₃ 523.2 25.0 96 468 1283 C₂₃H₂₇Cl₂N₃O₃ 464.2 12.2 53 469 1284 C₂₂H₂₈BrClN₃O₃ 496.0 24.1 97 470 1285 C₂₂H₂₅Cl₂N₃O₃ 450.2 21.8 97 471 1321 C₂₀H₂₀BrCl₂N₃O₂ 486.0 5.1 21 472 1322 C₂₁H₂₃Cl₂N₃O₂ 420.0 10.5 50 473 1323 C₂₀H₂₀Cl₂IN₃O₂ 532.0 7.1 27 474 1324 C₂₁H₂₄ClN₃O₃ 402.2 22.2 Q 475 1325 C₂₇H₂₆ClN₃O₃ 476.0 22.2 93 476 1326 C₂₀H₂₁ClIN₃O₃ 514.0 26.9 Q 477 1327 C₂₁H₂₅ClN₄O₂ 401.2 24.2 Q 478 1328 C₂₁H₂₃BrClN₃O₂ 466.0 23.1 99 479 1329 C₂₂H₂₆ClN₃O₂ 400.2 16.4 82 480 1330 C₂₁H₂₃ClIN₃O₂ 512.2 20.8 81 481 1331 C₂₁H₂₄N₃O₃ 382.2 19.6 Q 482 1332 C₂₈H₂₉N₃O₃ 456.2 21.1 93 483 1333 C₂₁H₂₄IN₃O₃ 494.0 25.3 Q 484 1334 C₂₂H₂₈N₄O₂ 381.2 19.0 Q 485 1335 C₁₉H₂₂BrClN₄O₃ 471.0 25.8 Q 486 1336 C₂₀H₂₅ClN₄O₃ 405.2 18.5 91 487 1337 C₁₉H₂₂ClIN₄O₃ 517.0 23.1 89 488 1338 C₂₀H₂₆N₄O₄ 387.2 20.6 Q 489 1339 C₂₆H₂₈N₄O₄ 461.2 23.7 Q 490 1340 C₁₉H₂₃IN₄O₄ 499.0 28.2 Q 491 1341 C₂₀H₂₆N₄O₄ 386.0 20.5 Q 492 1342 C₂₂H₂₄BrCl₂N₃O₂ 514.0 27.2 Q 493 1343 C₂₃H₂₇Cl₂N₃O₂ 448.0 21.4 95 494 1344 C₂₂H₂₄Cl₂IN₃O₂ 560.0 27.0 96 495 1345 C₂₃H₂₈ClN₃O₃ 430.2 23.8 Q 496 1346 C₂₂H₂₅ClIN₃O₃ 542.0 29.4 Q 497 1347 C₁₉H₂₂ClN₃O₂S 392.0 16.9 43 498 1348 C₂₀H₂₅N₃O₂S 372.2 6.9 19 499 1349 C₁₈H₂₄N₄O₃S 377.2 8.1 43 500 1350 C₂₁H₂₆ClN₃O₂S 420.0 13.0 62 501 1351 C₂₂H₂₄BrClN₄O₃ 509.2 5.0 10 502 1352 C₂₃H₂₇BrN₄O₃ 489.2 3.6 15 503 1353 C₂₁H₂₆BrN₅O₄ 494.0 2.8 11 504 1354 C₂₄H₂₈BrClN₄O₃ 537.2 5.2 19 505 1355 C₂₁H₂₂ClN₅O₂ 412.0 25.5 Q 506 1356 C₂₂H₂₅N₅O₂ 392.0 16.5 84 507 1357 C₂₀H₂₄N₆O₃ 397.2 19.9 Q 508 1358 C₂₃H₂₆ClN₅O₂ 440.2 21.8 99 509 1368 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 18.4 78 510 1369 C₂₄H₂₄ClF₆IN₃O₄ 568.0 24.1 85 511 1370 C₁₈H₁₉BrClN₃O₂S 458.0 19.4 85 512 1371 C₂₆H₂₆ClN₃O₄S 512.2 22.1 86 513 1372 C₂₆H₂₆ClN₃O₂ 448.0 19.1 85 514 1373 C₂₂H₂₃ClF₃N₃O₂ 454.2 16.2 71 515 1374 C₂₅H₂₇F₆IN₃O₄ 548.2 22.1 81 516 1375 C₁₉H₂₂BrN₃O₂S 436.0 17.1 78 517 1376 C₂₇H₂₉N₃O₄S 492.0 19.4 79 518 1377 C₂₇H₂₉N₃O₂ 428.2 18.1 85 519 1378 C₂₀H₂₂ClF₃N₄O₃ 459.0 17.3 75 520 1379 C₂₃H₂₆F₆IN₄O₅ 553.2 21.0 76 521 1380 C₁₇H₂₁BrN₄O₃S 443.0 16.4 74 522 1381 C₂₅H₂₈N₄O₅S 497.0 18.4 74 523 1382 C₂₅H₂₈N₄O₃ 433.2 17.3 80 524 1383 C₂₃H₂₄Cl₂F₃N₃O₂ 502.0 20.0 80 525 1384 C₂₀H₂₃BrClN₃O₂S 486.0 21.0 87 526 1385 C₂₈H₃₀ClN₃O₄S 540.2 23.8 88 527 1386 C₂₈H₃₀ClN₃O₂ 476.0 20.0 84 528 1411 C₂₂H₂₄Cl₂N₄O₃ 463.0 0.4  2 529 1412 C₂₃H₂₇ClN₄O₂ 443.0 1.3  6 530 1413 C₂₁H₂₆ClN₅O₄ 448.0 1.1  5 531 1414 C₂₄H₂₈Cl₂N₄O₃ 491.0 0.8  3 532 1415 C₂₁H₂₂ClN₅O₂S 444.0 6.8 31 533 1416 C₂₂H₂₅N₅O₂S 424.0 4.8 23 534 1417 C₂₀H₂₄N₆O₃S 429.2 4.5 21 535 1418 C₂₃H₂₆ClN₆O₂S 472.0 10.4 44 536 1423 C₂₇H₂₆ClN₃O₃ 476.0 23.9 Q 537 1424 C₂₇H₂₉N₃O₄S 456.2 28.0 Q 538 1425 C₂₆H₂₈N₄O₄ 461.2 22.3 97 539 1426 C₂₉H₃₀ClN₃O₃ 504.2 26.8 Q 540 1583 C₂₁H₂₂ClF₃N₄O₂ 455.0 14.6 64 541 1584 C₂₁H₂₂ClF₃N₄O₃ 471.0 17.4 74 542 1585 C₁₉H₂₀BrClN₄O₂ 453.0 15.6 69 543 1586 C₁₉H₂₀Cl₂N₄O₂ 407.2 2.3 11 544 1587 C₂₆H₂₆ClN₃O₃ 464.0 15.4 66 545 1588 C₂₀H₂₃ClN₄O₂ 387.0 14.8 77 546 1589 C₂₂H₂₅F₃N₄O₂ 435.2 11.1 51 547 1590 C₂₀H₂₅F₃N₄O₃ 451.2 16.3 72 548 1591 C₂₀H₂₃BrN₄O₂ 433.0 15.4 71 549 1592 C₂₀H₂₃ClN₄O₂ 387.0 15.6 81 550 1593 C₂₇H₂₉N₃O₃ 444.2 14.8 67 551 1594 C₂₀H₂₄F₃N₅O₃ 440.2 16.2 74 552 1595 C₂₀H₂₄F₃N₅O₄ 456.2 15.4 68 553 1596 C₁₈H₂₂BrN₅O₃ 436.0 15.6 72 554 1597 C₁₈H₂₂ClN₅O₃ 391.8 14.4 73 555 1598 C₂₅H₂₈N₄O₄ 449.2 15.9 71 556 1599 C₁₉H₂₅N₅O₃ 372.2 15.8 85 557 1606 C₂₁H₂₁ClF₃N₃O₂S 472.0 17.0 72 558 1607 C₂₁H₂₁ClF₃N₃O₂S 452.2 15.3 68 559 1608 C₂₀H₂₃F₃N₄O₃S 457.2 15.9 70 560 1660 C₂₁H₂₂BrF₃N₄O₂ 501.0 19.0 76 561 1661 C₂₁H₂₂BrF₃N₄O₃ 517.0 16.2 63 562 1662 C₂₀H₂₁BrF₂N₄O₂ 469.0 15.1 65 563 1663 C₂₀H₂₂BrClN₄O₂ 467.0 14.5 62 564 1692 C₂₀H₂₃Br₂N₃O₂ 514 7.3 28 565 1693 C₂₂H₂₆F₂N₄O₂ 417 16.2 78 566 1694 C₂₂H₂₇FN₄O₂ 399 21.8 Q 567 1695 C₂₂H₂₇BrN₄O₂ 459 24.5 Q 568 1696 C₂₂H₂₇IN₄O₂ 507 27.4 Q 569 1697 C₂₂H₂₇ClN₄O₂ 415 22.1 Q 570 1698 C₂₃H₂₇F₃N₄O₃ 465 24.3 Q 571 1699 C₂₃H₂₇F₃N₄O₂ 449 25.3 Q 572 1700 C₂₂H₂₅BrClN₃O₂ 480 17.8 74 Note: Q means “Quantitative”.

For example, Compd. No. 1583 exhibited the following NMR: ¹H NMR (400 MHz, CD₃₀D) δ 1.64-1.72 (m, 1H), 2.20-2.30 (m, 1H), 2.41-2.51 (m, 2H), 52.71-2.78 (m, 2H), 3.59 (dd, J=15.4, 12.9 Hz, 2H), 3.94 (s, 2H), 4.35-4.41 (m, 1H), 6.82 (d, J=8.6 Hz, 1H), 7.29 (s, 4H), 7.40 (dd, J=8.6, 1.7 Hz, 1H), 7.85 (d, J=0.96 Hz, 1H).

Reference Example 4 Synthesis of (S)-3-[N-[3-(trifluoromethyl)benzoyl]glycyl]aminopyrrolidine

A suspension of (S)-1-(4-chlorobenzyl)-3-[N-[3-(trifluoromethyl)benzoyl]glycyl]aminopyrrolidine (2.93 g. 6.66 mmol) and Pd(OH)₂ in a 5% formic acid/methanol (70 mL) was stirred at 60° C., for 3 hours. The palladium catalyst was removed by filtration through Celite to concentrate the filtrate. A 2 M solution of NaOH (100 mL) was added to the resulting residue, and the resulting mixture was extracted with ethyl acetate (100 mL×3). The extracts were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography [SiO₂, ethyl acetate/methanol/triethylamine=(85:10:5) to (60:30:5)] to thereby provide (S)-3-[N-3-(trifluoromethyl)benzoyl]glycyl]aminopyrrolidine (1.70 g, 81%) as an oil. ¹H NMR (CDCl₃, 270 MHz) δ 1.76 (d, J=7.3 Hz, 1H), 2.07-2.25 (m, 1H), 2.81-2.98 (m, 2H), 3.02-3.11 (m, 2H), 4.12 (s, 2H), 4.41 (br, 1H), 6.90 (br, 1H), 7.45 (br, 1H), 7.58 (dd, J=7.3 and 7.3 Hz, 1H), 7.77 (d, J=7.3 Hz, 1H), 8.02 (d, J=7.3 Hz, 1H), 8.11 (s, 1H); ESI/MS m/e 316.0 (M⁺+H, C₁₄H₁₆F₃N₃O₂).

Further, (R)-3-[N-[3-(trifluoromethyl)benzoyl]glycyl]aminopyrrolidine was synthesized by using the corresponding starting material and reactants according to the above method. 1.49 g, 68%. The product exhibited the same ¹H NMR and ESI/MS as those of the (S)-isomer.

In addition, (R)-3-[N-[2-amino-5-(trifluoromethyl)benzoyl]glycyl]aminopyrrolidine was synthesized by using the corresponding starting material and reactants according to the above method. 316 mg, 93%; ESI/MS m/e 331.2 (M⁺+H, C₁₄H₁₇F₃N₄O₂).

Moreover, (R)-3-[N-[2-(tert-butoxycarbonylamino)-5-(trifluoromethoxyl)benzoyl]glycyl]aminopyrrolidine was synthesized by using the corresponding starting material and reactants according to the above method. Quantitative yield; ¹H NMR (CDCl₃, 400 MHz) δ 1.51 (s, 9H), 1.60-1.70 (m, 2H), 2.10-2.25 (m, 1H), 2.80-2.88 (m, 1H), 2.89-2.98 (m, 1H), 3.04-3.18 (m, 2H), 4.05 (d, J=4.9 Hz, 2H), 4.43 (br, 1H), 6.15 (br, 1H), 7.03 (br, 1H), 7.32 (d, J=9.3 Hz, 1H), 7.38 (s, 1H), 8.42 (d, J=9.3 Hz, 1H).

Example 573 Synthesis of (R)-3-[[N-[2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl]glycyl]amino]-1-(4-chlorobenzyl)pyrrolidine

Triethylamine (2.9 mL, 20.5 mmol), 2-(tert-butoxycarbonylamino)-5-(trifluoromethyl)benzoic acid (6.27 g, 20.5 mmol), EDCI (3.9 g, 20.5 mmol) and HOBt (2.8 g, 20.5 mmol) were added to a dichloromethane (100 mL) solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (5.0 g, 18.7 mmol). The resulting reaction mixture was stirred at room temperature overnight. A 2 M aqueous solution (80 mL) of NaOH was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The obtained extract was dried over anhydrous Na₂SO₄, filtered, concentrated and purified by column chromatography [SiO₂, hexane/ethyl acetate=(1:1) to (1:4)] to thereby afford (R)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]-1-(4-chlorobenzyl)pyrrolidine (9.41 g, 91%) as a white amorphous solid. ESI/MS m/e 555.2 (M⁺+H, C₂₆H₃₀ClF₃N₄O₄).

Reference Example 5 Synthesis of (R)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine

A mixture of (R)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]-1-(4-chlorobenzyl)pyrrolidine (6.3 g, 11.4 mmol) with Pd(OH)₂ (1.68 g), formic acid (3.7 mL) and methanol (80 mL) was stirred at 50° C. overnight. The mixture was cooled to room temperature, and the palladium catalyst was then removed by filtration through Celite. The resulting filtrate was concentrated and purified by column chromatography [SiO₂, ethyl acetate/methanol=(5:1) to (4:1)] to thereby provide (R)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (4.42 g, 90%) as a white solid. ¹H NMR (CDCl₃, 400 MHz) δ 1.48 (s, 9H), 2.0-2.4 (m, 2H), 3.42-3.71 (m, 5H), 4.00-4.22 (m, 2H), 4.56 (br, 1H), 7.48 (d, J=9.0 Hz, 1H), 7.93 (s, 1H), 8.17 (br, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.45 (br, 1H).

Example 574 Synthesis of (S)-1-benzyl-3-[N-[3-(trifluoromethyl)benzoyl]glycyl]aminopyrrolidine (Compd. No. 239)

An acetonitrile (1.1 mL) solution of (S)-3-[N-[3-(trifluoromethyl)benzoyl]glycyl]aminopyrrolidine (0.06 mmol) and a (piperidinomethyl)polystyrene (2.6 to 2.8 mmol/g, 30 mg) were added to an acetonitrile (0.4 mL) solution of benzyl bromide (0.050 mmol). The resulting reaction mixture was stirred at 45° C. for 5 hours. The mixture solution was cooled to room temperature, and the resin was then removed by filtration to concentrate the filtrate. The resulting residue was dissolved in acetonitrile (1.0 mL), and phenyl isocyanate (0.008 mL, 0.05 mmol) was then added to the obtained solution. The mixture solution was stirred at room temperature for 1 hour, loaded onto a Varian™ SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a solution of 2 M NH₃ in methanol (6 mL) and concentrated to thereby provide (S)-1-benzyl-3-[N-[3-(trifluoromethyl)benzoyl]glycyl]aminopyrrolidine (Compd. No. 239) (9.0 mg, 44%). The purity was determined by RPLC/MS (99%). ESI/MS m/e 406.0 (M⁺+H, C₂₁H₂₂F₃N₃O₂).

Example 575 Synthesis of (R)-1-(4-butylbenzyl)-3-[[N-(3-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (Compd. No. 1648)

Acetic acid (0.060 mL) was added to a mixture of (R)-3-[N-[3-(trifluoromethyl)benzoyl]glycyl]aminopyrrolidine (0.050 mL) with 4-butylbenzaldehyde (0.18 mmol), NaBH₃CN (0.23 mmol) and methanol (1.85 mL). The resulting reaction mixture was stirred at 60° C. for 12 hours, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a solution of 2 M NH₃ in methanol (5 mL) and concentrated to thereby afford (R)-1-(4-butylbenzyl)-3-[[N-(3-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (Compd. No. 1648) (20.6 mg, 89%). The purity was determined by RPLC/MS (91%). ESI/MS m/e 462.2 (M⁺+H, C₂₅H₃₀F₃N₃O₂).

Examples 576 to 738

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 574 or 575. The obtained crude products, if necessary, were purified by preparative TLC or chromatography (HPLC-C₁₈) to provide the objective compounds. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 8.

TABLE 8 ESI/MS Yield Yield Example Compd. No. Molecular Formula m/e (mg) (%) 576 240 C₂₁H₂₁F₄N₃O₂ 424.0 10.2 48 577 241 C₂₁H₂₁ClF₃N₃O₂ 440.0 12.1 55 578 242 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 13.9 59 579 243 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 13.8 58 580 244 C₂₂H₂₄F₃N₃O₂ 420.0 13.1 62 581 245 C₂₁H₂₁F₄N₃O₂ 424.0 11.9 56 582 246 C₂₁H₂₁ClF₃N₃O₂ 440.0 8.5 39 583 247 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 10.5 44 584 248 C₂₂H₂₄CF₃N₃O₃ 436.0 11.0 51 585 249 C₂₂H₂₁ClF₆N₃O₂ 474.0 12.8 54 586 250 C₂₂H₂₄F₃N₃O₂ 420.0 11.0 52 587 251 C₂₁H₂₁F₄N₃O₂ 424.0 13.5 64 588 252 C₂₂H₂₄F₃N₃O₃ 436.0 11.8 54 589 253 C₂₂H₂₄F₃N₃O₂ 420.0 11.1 53 590 254 C₂₁H₂₀ClF₃N₄O₄ 485.0 2.4 10 591 255 C₂₁H₂₁F₃N₄O₄ 451.0 12.2 54 592 256 C₂₁H₂₁F₃N₄O₄ 451.0 11.4 51 593 257 C₂₂H₂₁F₆N₃O₂ 474.0 11.1 47 594 258 C₂₄H₂₆F₃N₃O₄ 478.0 15.3 64 595 259 C₂₂H₂₃ClF₃N₃O₂ 420.0 6.4 31 596 260 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 12.1 51 597 261 C₂₂H₂₁ClF₆N₃O₂ 474.0 13.6 57 598 262 C₂₁H₂₁BrF₃N₃O₂ 484.0 15.2 63 599 263 C₂₁H₂₁BrF₃N₃O₂ 484.0 14.5 60 600 264 C₂₇H₂₆F₃N₃O₃ 498.0 9.3 37 601 265 C₂₁H₂₁BrF₃N₃O₂ 484.0 11.6 48 602 266 C₂₂H₂₂F₃N₃O₄ 450.0 8.9 40 603 267 C₂₂H₂₄F₃N₃O₃ 436.0 10.3 47 604 268 C₂₃H₂₅F₃N₄O₃ 463.0 6.3 27 605 269 C₂₂H₂₄F₃N₃O₄S 484.0 8.0 33 606 270 C₂₃H₂₄F₃N₃O₄ 464.0 8.9 38 607 271 C₂₁H₂₀F₆N₃O₂ 442.0 6.1 28 608 272 C₂₁H₂₂F₃N₃O₃ 422.0 13.6 59 609 273 C₂₂H₂₁F₃N₄O₂ 431.0 12.6 59 610 274 C₂₂H₂₁F₃N₄O₂ 431.0 7.7 36 611 275 C₂₂H₂₁F₃N₄O₂ 431.0 12.7 59 612 276 C₂₁H₂₀F₅N₃O₂ 442.0 11.7 53 613 277 C₂₇H₂₆F₃N₃O₂ 482.0 9.5 39 614 278 C₂₃H₂₄F₃N₃O₄ 464.0 13.0 56 615 279 C₂₂H₂₁F₆N₃O₃ 490.0 10.4 42 616 280 C₂₂H₂₁F₆N₃O₃ 490.0 12.0 49 617 281 C₂₂H₂₂F₃N₃O₄ 450.0 4.9 22 618 282 C₂₅H₃₀F₃N₃O₂ 462.0 12.0 52 619 283 C₂₀H₂₃F₃N₄O₃ 425.0 8.1 38 620 284 C₂₇H₂₅ClF₃N₃O₂ 516.0 4.8 19 621 285 C₂₁H₂₂F₃N₃O₂ 406.0 4.8 24 622 286 C₂₁H₂₁F₄N₃O₂ 424.0 4.5 21 623 287 C₂₁H₂₁ClF₃N₃O₂ 440.0 5.8 26 624 288 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 8.1 34 625 289 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 8.0 34 626 290 C₂₂H₂₄F₃N₃O₂ 420.0 6.0 29 627 291 C₂₁H₂₁F₄N₃O₂ 424.0 6.2 29 628 292 C₂₁H₂₁ClF₃N₃O₂ 440.0 4.5 20 629 293 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 5.1 22 630 294 C₂₂H₂₄CF₃N₃O₃ 436.0 4.2 19 631 295 C₂₂H₂₁ClF₆N₃O₂ 474.0 6.0 25 632 296 C₂₂H₂₄F₃N₃O₂ 420.0 4.3 21 633 297 C₂₁H₂₁F₄N₃O₂ 424.0 8.2 39 634 298 C₂₂H₂₄F₃N₃O₃ 436.0 12.2 56 635 299 C₂₂H₂₄F₃N₃O₂ 420.0 8.1 39 636 300 C₂₁H₂₀ClF₃N₄O₄ 485.0 13.7 57 637 301 C₂₁H₂₁F₃N₄O₄ 451.0 15.1 67 638 302 C₂₁H₂₁F₃N₄O₄ 451.0 16.6 74 639 303 C₂₂H₂₁F₆N₃O₂ 474.0 12.6 53 640 304 C₂₄H₂₆F₃N₃O₄ 478.0 14.5 61 641 305 C₂₂H₂₃ClF₃N₃O₂ 420.0 8.4 37 642 306 C₂₁H₂₀Cl₂F₃N₃O₂ 474.0 13.5 57 643 307 C₂₂H₂₁ClF₆N₃O₂ 474.0 3.7 16 644 308 C₂₁H₂₁BrF₃N₃O₂ 484.0 7.2 30 645 309 C₂₁H₂₁BrF₃N₃O₂ 484.0 6.7 28 646 310 C₂₇H₂₆F₃N₃O₃ 498.0 4.2 17 647 311 C₂₁H₂₁BrF₃N₃O₂ 484.0 6.3 26 648 312 C₂₂H₂₂F₃N₃O₄ 450.0 2.4 11 649 313 C₂₂H₂₄F₃N₃O₃ 436.0 1.9  9 650 314 C₂₃H₂₅F₃N₄O₃ 463.0 5.0 22 651 315 C₂₂H₂₄F₃N₃O₄S 484.0 2.5 10 652 316 C₂₃H₂₄F₃N₃O₄ 464.0 3.3 14 653 317 C₂₁H₂₀F₅N₃O₂ 442.0 4.5 20 654 318 C₂₁H₂₂F₃N₃O₃ 422.0 7.9 34 655 319 C₂₂H₂₁F₃N₄O₂ 431.0 6.5 30 656 320 C₂₂H₂₁F₃N₄O₂ 431.0 14.2 66 657 321 C₂₂H₂₁F₃N₄O₂ 431.0 14.9 69 658 322 C₂₁H₂₀F₅N₃O₂ 442.0 13.6 62 659 323 C₂₇H₂₆F₃N₃O₂ 482.0 3.9 16 660 324 C₂₃H₂₄F₃N₃O₄ 464.0 15.2 66 661 325 C₂₂H₂₁F₆N₃O₃ 490.0 16.1 66 662 326 C₂₂H₂₁F₆N₃O₃ 490.0 13.6 56 663 327 C₂₂H₂₂F₃N₃O₄ 450.0 5.4 24 664 328 C₂₆H₃₀F₃N₃O₂ 462.0 10.9 47 665 329 C₂₀H₂₃F₃N₄O₃ 425.0 12.0 57 666 986 C₂₇H₂₅ClF₃N₃O₂ 516.0 1.5  6 667 1118 C₂₈H₂₇F₃N₄O₃ 525 21.5 62 668 1119 C₂₂H₂₄F₃N₃O₂S 452 16.9 57 669 1120 C₂₃H₂₆F₃N₃O₄ 466 20.5 67 670 1121 C₂₂H₂₃F₃N₄O₄ 465 16.8 55 671 1122 C₂₈H₃₆F₃N₃O₂ 504 21.0 63 672 1123 C₂₅H₂₃BrF₃N₃O₂ 534 26.6 75 673 1124 C₁₉H₁₉F₃N₄O₅ 441 21.3 73 674 1133 C₂₃H₂₆F₃N₃O₄ 467 33.6 84 675 1134 C₂₄H₂₈F₃N₃O₅ 496 34.8 82 676 1135 C₂₂H₂₁F₃N₄O₆ 495 32.6 77 677 1136 C₂₃H₂₄F₃N₃O₅ 480 36.6 89 678 1137 C₂₂H₂₁BrF₃N₃O₄ 529 30.8 69 679 1138 C₂₄H₂₆F₃N₃O₂ 446 32.7 86 680 1139 C₂₂H₂₄F₃N₃O₂ 420 18.6 51 681 1140 C₂₁H₂₀F₃N₅O₆ 496 20.5 49 682 1141 C₂₅H₂₄F₃N₃O₂ 456 22.5 58 683 1142 C₂₅H₂₄F₃N₃O₂ 456 21.6 55 684 1143 C₃₅H₃₄F₃N₃O₄ 618 27.3 53 685 1144 C₂₃H₂₆F₃N₃O₄ 466 25.5 64 686 1145 C₂₃H₂₅F₃N₄O₆ 511 38.0 88 687 1146 C₂₈H₂₈F₃N₃O₃ 512 38.3 89 688 1147 C₂₃H₂₅F₃N₄O₃ 463 27.1 62 689 1148 C₂₇H₂₆F₃N₃O₂ 482 22.4 57 690 1161 C₂₂H₂₄F₃N₃O₄ 452 13.5 58 691 1162 C₂₄H₂₈F₃N₃O₃ 464 16.7 70 692 1163 C₂₂H₂₃F₄N₃O₃ 454 15.8 68 693 1164 C₂₃H₂₆F₃N₃O₃ 450 15.7 68 694 1165 C₂₃H₂₄F₃N₃O₄ 464 16.3 68 695 1166 C₂₂H₂₃BrF₃N₃O₃ 513 15.0 57 696 1168 C₁₇H₁₇ClF₃N₅O₂S 448 6.9* 23 697 1169 C₂₀H₂₂F₃N₅O₃S 470 1.7*  6 698 1170 C₂₂H₂₂F₃N₅O₂ 446 2.3*  8 699 1286 C₂₆H₃₃F₃N₄O₃ 507 25.3* 51 700 1287 C₂₁H₂₀F₃N₅O₆ 496 4.0*  8 701 1288 C₂₂H₂₄F₃N₃O₄ 452 3.6* 13 702 1298 C₂₃H₂₅BrF₃N₃O₄ 544 28.4 Q 703 1299 C₂₄H₂₈F₃N₃O₅ 496 1.4  6 704 1300 C₂₃H₂₆F₃N₃O₄ 466 7.3 33 705 1301 C₂₄H₂₈F₃N₃O₅ 496 12.6 53 706 1302 C₂₄H₂₈F₃N₃O₃ 464 24.5 Q 707 1303 C₂₃H₂₅BrF₃N₃O₄ 544 22.2 Q 708 1304 C₂₉H₃₀F₃N₃O₄ 542 28.6 Q 709 1305 C₂₆H₂₆F₃N₃O₃ 486 35.4 Q 710 1306 C₂₄H₂₈F₃N₃O₄ 480 8.1 35 711 1307 C₂₃H₂₆F₃N₃O₅ 482 27.9 Q 712 1308 C₂₃H₂₄F₃N₃O₃ 448 5.9 28 713 1309 C₂₃H₂₅F₃IN₃O₄ 592 24.0 85 714 1310 C₂₂H₂₄F₃N₃O₄ 452 3.4 16 715 1311 C₂₂H₂₂F₃N₃O₄ 450 3.4 16 716 1312 C₂₁H₂₁F₃IN₃O₂ 532 18.1 72 717 1313 C₂₁H₂₁BrF₃N₃O₂ 484 17.4 76 718 1314 C₁₉H₁₉F₃N₄O₄S 457 16.8 77 719 1315 C₂₀H₂₂F₃N₃O₃ 410 13.6 70 720 1316 C₂₂H₂₀ClF₆N₃O₂ 508 18.6 77 721 1317 C₂₁H₂₀ClF₃N₄O₄ 485 17.0 74 722 1318 C₂₁H₂₀ClF₄N₃O₂ 458 17.0 78 723 1319 C₂₁H₂₀ClF₄N₃O₂ 458 17.6 81 724 1320 C₂₁H₂₀BrF₄N₃O₂ 502 18.5 77 725 1390 C₂₆H₃₂F₃N₃O₂ 476 16.1 51 726 1391 C₂₃H₂₆F₃N₃O₂ 434 20.0 76 727 1392 C₂₂H₂₃ClF₃N₃O₂ 454 20.0 67 728 1393 C₂₃H₂₆F₃N₃O₂ 434 20.1 70 729 1394 C₂₂H₂₃F₃N₄O₄ 465 18.4 60 730 1395 C₂₃H₂₄F₃N₃O₂ 432 21.4 75 731 1396 C₂₆H₂₆F₃N₃O₂ 470 20.4 66 732 1397 C₂₁H₂₀Br₂F₃N₃O₂ 562 14.5 54 733 1398 C₂₂H₂₂Cl₂F₃N₃O₂ 488 10.8 47 734 1399 C₂₂H₂₂Cl₂F₃N₃O₂ 488 9.4 40 735 1400 C₂₂H₂₃ClF₃N₃O₂ 454 19.1 88 736 1614 C₂₂H₂₁F₆N₃S 506.0 24.2 96 737 2050 C₂₀H₂₂F₃N₃O₂S 426 6.0 30 738 2051 C₂₁H₂₃F₃N₄O₂ 421 6.5 32 Notes: *indicates “yield (mg) of trifluoroacetate”. Q means “Quantitative”.

Examples 739 to 748

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 575. The obtained products, if necessary, were purified with preparative TLC to afford the objective compounds. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 9.

TABLE 9 Molecular ESI/MS Yield Example Compd. No. Formula m/e (mg) Yield (%) 739 1650 C₂₄H₂₈F₃N₃O₂ 448.0 20.4 91 740 1706 C₂₃H₂₅F₃N₄O₃ 463.2 3.7 11 741 1707 C₂₂H₂₅F₃N₄O₂S 467.0 10.3 29 742 1708 C₂₃H₂₇F₃N₄O₂ 449.2 11.4 34 743 1709 C₂₄H₂₉F₃N₄O₂ 463.2 15.2 44 744 1775 C₂₂H₂₅F₃N₄O₄ 467.2 9.2 26.3 745 1776 C₂₂H₂₅F₃N₄O₄ 467.2 8.9 25.4 746 1787 C₂₄H₂₉F₃N₄O₂ 463.2 5.6 16.1 747 1802 C₂₃H₂₇F₃N₄O₄ 481.2 11.7 32.5 748 1803 C₂₂H₂₅F₃N₄O₃ 451.2 9.6 28.4

Example 749 Synthesis of (R)-3-[[N-2-amino-5-trifluoromethoxybenzoyl)glycyl]amino]-1-(3-hydroxy-4-methoxybenzyl)pyrrolidine (Compd. No. 1896)

Acetic acid (0.050 mL) was added to a mixture of (R)-3-[N-[2-(tert-butoxycarbonylamino)-5-(trifluoromethoxybenzoyl)glycyl]amino]pyrrolidine (0.050 mmol) with 3-hydroxy-4-methoxybenzaldehyde (0.060 mmol), NaBH₃CN (0.15 mmol) and methanol (1.3 mL). The resulting reaction mixture was stirred at 60° C. for 8 hours, cooled to room temperature, then loaded onto a Varian™ SCX column and washed with methanol (10 mL). The obtained crude product was eluted with a solution of 2 M NH₃ in methanol (5 mL) and concentrated. A 1,4-dioxane solution of 4 M HCl was added to the prepared residue, and the solution was stirred at room temperature overnight, concentrated and then purified by preparative TLC to thereby provide (R)-3-[[N-(2-amino-5-trifluoromethoxybenzoyl)glycyl]amino]-1-(3-hydroxy-4-methoxybenzyl)pyrrolidine (Compd. No. 1896) (9.1 mg, 38%). The purity was determined by RPLC/MS (93%). ESI/MS m/e 483 (M⁺+H, C₂₂H₂₅F₃N₄O₅).

Examples 750 to 757

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 749. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 10.

TABLE 10 Molecular ESI/MS Yield Example Compd. No. Formula m/e (mg) Yield (%) 750 1897 C₂₂H₂₅F₃N₄O₃S 483 22.7 94.1 751 1898 C₂₃H₂₇F₃N₄O₃ 465 12.2 52.5 752 1899 C₂₄H₂₉F₃N₄O₃ 479 14.4 60.2 753 1900 C₂₂H₂₅F₃N₄O₅ 483 2.6 10.8 754 1901 C₂₄H₂₉F₃N₄O₃ 479 14.5 60.6 755 1902 C₂₃H₂₅F₃N₄O₄ 479 12.0 50.2 756 1915 C₂₃H₂₇F₃N₄O₅ 467.2 2.5 6.7 757 1916 C₂₂H₂₅F₃N₄O₄ 467.2 3.1 8.9

Example 758 Synthesis of (R)-3-[[N-(2-amino-5-trifluoromethyl)benzoyl)glycyl]amino]-1-(4-vinylbenzyl)pyrrolidine (Compd. No. 1701)

A mixture of (R)-3.-[[N-(2-amino-5-(trifluoromethyl)benzoyl)glycyl]amino]pyrrolidine (0.050 mmol) with 4-vinylbenzyl chloride (9.9 mg, 0.065 mL), a piperidinopolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.30 mL) was stirred at 50° C. for 12 hours. The resulting reaction mixture was cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (15 mL). The obtained crude product was eluted with solution of 2 M NH₃ in a methanol (5 mL) and concentrated to thereby afford (R)-3-[[N-(2-amino-5-(trifluoromethyl)benzoyl)glycyl]amino]-1-(4-vinylbenzyl)pyrrolidine (Compd. No. 1701) (19.6 mg, 88%). The purity was determined by RPLC/MS (92%). ESI/MS m/e 547.2 (M⁺+H, C₂₃H₂₅ClF₃N₄O₂).

Examples 759 to 762

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 758. The obtained products, if necessary, were purified with preparative TLC to provide the objective substances. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 11.

TABLE 11 ESI/MS Yield Yield Example Compd. No. Molecular Formula m/e (mg) (%) 759 1702 C₂₂H₂₅F₃N₄O₃ 451.2 5.3 24 760 1703 C₂₂H₂₃F₃N₄O₄ 465.2 5.0 22 761 1704 C₂₁H₂₃F₃N₄O₃ 437.2 20.9 96 762 1705 C₂₁H₂₁Cl₂F₃N₄O₂ 489.2 9.3 38

Example 763 Synthesis of (R)-3-[[N-(2-amino-5-(trifluoromethoxy)benzoyl)glycyl]amino]-1-(2,4-dichlorobenzyl)pyrrolidine (Compd. No. 1905)

A mixture of (R)-3-[[N-(2-amino-5-(trifluoromethoxyl)benzoyl)glycyl]amino]pyrrolidine (0.050 mmol) with 2,4-dichlorobenzyl chloride (0.066 mL), a piperidinomethylpolystyrene (60 mg), acetonitrile (0.8 mL) and chloroform (0.5 mL) was stirred at 60° C. for 12 hours. The resulting reaction mixture was cooled to room temperature, loaded onto a Varian™ SCX column and washed with a 50% chloroform/methanol (10 mL) and methanol (10 mL). The obtained crude product was eluted with a solution of 2 M NH₃ in methanol (5 mL) and concentrated. A 1,4-dioxane (2 mL) solution of 4 M HCl was added to the resulting residue, and the obtained mixture was stirred at room temperature overnight, concentrated and then purified by preparative TLC to afford (R)-3-[[N-(2-amino-5-(trifluoromethoxy)benzoyl]glycyl]amino]-1-(2,4-dichlorobenzyl)pyrrolidine (Compd. No. 1905) (17.6 mg, 70%). The purity was determined by RPLC/MS (93%). ESI/MS m/e 505 (M⁺+H, C₂₁H₂₁Cl₂F₃N₄O₃).

Examples 764 to 770

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 763. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 12.

TABLE 12 Molecular ESI/MS Yield Example Compd. No. Formula m/e (mg) Yield (%) 764 1906 C₂₂H₂₃F₃N₄O₅ 481 9.4 39.1 765 1907 C₂₁H₂₃F₃N₄O₄ 453 7.5 33.2 766 1908 C₂₂H₂₅F₃N₄O₄ 467 7.7 33.0 767 2180 C₂₂H₂₄ClF₃N₄O₂ 469 1.3 26 768 2181 C₂₃H₂₅F₃N₆O₃ 491 4.3 52 769 2182 C₁₉H₂₂F₃N₅O₂S 442 7.0 51 770 1909 C₂₃H₂₅F₃N₄O₃ 463 8.7 37.6

Example 771 Synthesis of (R)-3-[[N-(2-amino-5-trifluoromethoxybenzoyl)glycyl]amino]-1-(2-amino-4-chlorobenzyl)pyrrolidine (Compd. No. 1921)

A mixture of (R)-3-[[N-(2-amino-5-trifluoromethoxybenzoyl)glycyl]amino]pyrrolidine (0.050 mmol) with 4-chloro-2-nitrobenzyl chloride (0.050 mmol), a piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.7 mL) was stirred at 50® C. overnight. The resulting reaction mixture was cooled, loaded onto a Varian™ SCX column and washed with 50% chloroform/methanol (10 mL) and methanol (10 mL). The obtained crude product was eluted with a solution of 2 M NH₃ in methanol (5 mL) and concentrated. Ethanol (3 mL) and 10% palladium carbon were added to the resulting residue, and the solution was stirred at room temperature under a hydrogen atmosphere for 1.5 hours. The obtained solution was filtered, concentrated and then purified by preparative TLC to thereby provide (R)-3-[[N-(2-amino-5-trifluoromethoxybenzoyl)glycyl]amino]-1-(2-amino-4-chlorobenzyl)pyrrolidine (Compd. No. 1921) (2.2 mg, 6%). The purity was determined by RPLC/MS (81%). ESI/MS m/e 486.2 (M⁺+H, C₂₁H₂₃ClF₃N₅O₃).

Example 772 Synthesis of (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-(4-bromo-2-fluorobenzyl)pyrrolidine (Compd. No. 2120)

A methanol (0.50 mL) solution of NaBH₃CN (0.25 mmol) was added to a mixture of (R)-3-[[N-(2-tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (0.050 mmol) with 4-bromo-2-fluorobenzaldehyde (0.015 mmol), methanol (1.5 mL) and acetic acid (0.016 mL). The resulting reaction mixture was stirred at 50° C. overnight, cooled to room temperature, then loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained product was eluted with a solution of 2 M NH₃ in methanol (5 mL) and concentrated. The resulting residue was dissolved in methanol (0.25 mL), and a dioxane solution of 4 M HCl was added to the obtained solution. The resulting solution was stirred at room temperature for 5 hours and concentrated. The obtained residue was dissolved in methanol, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The resulting crude product was eluted with a solution of 2 M NH₃ in methanol (5 mL) and concentrated. The obtained residue was dissolved in ethyl acetate (0.5 mL), loaded onto a Varian™ SCX column, eluted with ethyl acetate/methanol=5:1 (6 mL) and concentrated to thereby afford (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-(4-bromo-2-fluorobenzyl)pyrrolidine (Compd. No. 2120) (16.0 mg, 31%). The purity was determined by RPLC/MS (99%). ESI/MS m/e 517.0 (M⁺+H, C₂₁H₂₁BrF₄N₄O₂).

Examples 773 to 793

The compounds used in the present invention were synthesized by using the respective starting materials and reactants according to the method of Example 772. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 13.

TABLE 13 Molecular ESI/MS Yield Example Compd. No. Formula m/e (mg) Yield (%) 773 2083 C₂₂H₂₄BrF₃N4O4 545.2 2.9 11 774 2084 C₂₃H₂₇F₃N₄O₅ 497.2 5.1 21 775 2085 C₂₂H₂₅F₃N₄O₄ 467.2 3.1 13 776 2086 C₂₁H₂₂ClF₃N₄O₃ 471.0 4.6 20 777 2087 C₂₃H₂₈F₃N₅O₂ 464.2 5.6 24 778 2088 C₂₅H₃₂F₃N₅O₂ 492.2 5.9 24 779 2089 C₂₁H₂₁F₅N₄O₂ 457.2 4.5 20 780 2090 C₂₇H₂₇F₃N₄O₃ 513.2 8.0 31 781 2118 C₂₁H₂₃F₃N₄O₄ 453.1 2.7 12 782 2119 C₂₁H₂₃F₃N₄O₄ 453.1 4.3 19 783 2121 C₂₂H₂₅F₃N₄O₄ 467.0 1.2  2 784 2122 C₂₁H₂₁ClF₄N₄O₂ 472.9 13.1 28 785 2123 C₂₂H₂₂F₃N₅O₆ 510.1 13.1 51 786 2124 C₂₁H₂₁ClF₃N₅O₄ 500.1 15.6 62 787 2125 C₂₂H₂₄F₃N₅O₅ 496.0 16.0 65 788 2126 C₂₂H₂₄F₃N₅O₄ 480.1 15.6 65 789 2137 C₂₂H₂₄ClF₃N₄O₂ 469.2 2.6 11 790 2138 C₂₆H₂₉F₃N₆O₂ 515.3 25.1 98 791 2139 C₂₀H₂₄ClF₃N₆O₂ 473.2 25.0 98 792 2149 C₂₁H₂₂F₃N₅O₅ 482.3 4.9 34 793 2157 C₂₂H₂₅F₃N₄O₃ 451.2 15.5 70

Example 794 Synthesis of (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-(2,4-dimethoxypyrimidin-5-ylmethyl)pyrrolidine (Compd. No. 2175)

(R)-3-[[N-(2-Amino-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (17.2 mg, 0.04 mmol) was dissolved in THF (1 mL), and 2,4-dimethoxy-5-pyrimidinecarboxaldehyde (6.7 mg, 0.04 mmol) was added to the resulting solution. Sodium triacetoxyborohydride (12.7 mg, 0.06 mmol) and glacial acetic acid (2.4 mg, 0.04 mmol) were subsequently added to the mixture. The resulting mixture was stirred at 50° C. for 24 hours and then concentrated. The residue was dissolved in dichloromethane (1 mL) and washed with a 1 M aqueous solution (1 mL) of NaOH. The organic layer was collected and concentrated, and a dichloromethane solution of 25% trifluoroacetic acid (1 mL) was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated. The obtained residue was purified by HPLC to thereby provide (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-(2,4-dimethoxypyrimidin-5-ylmethyl)pyrrolidine (Compd. No. 2175) (18.6 mg, 78%). The purity was determined by RPLC/MS (98%). ESI/MS m/e 483 (M⁺+H, C₂₁H₂₅F₃N₆O₄).

Examples 795 to 803

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according the method of Example 794. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 14.

TABLE 14 ESI/MS Yield Yield Example Compd. No. Molecular Formula m/e (mg) (%) 795 2165 C₁₈H₂₁F₃N₆O₂ 411 2.0 27 796 2166 C₁₈H₂₀F₃N₅O₂S 428 9.9 66 797 2167 C₂₄H₂₅F₃N₆O₂ 487 15.1 73 798 2169 C₂₄H₂₉F₃N₄O₂ 463 1.2 24 799 2170 C₂₆H₂₅ClF₃N₅O₂ 520 6.0 40 800 2171 C₁₉H₂₃F₃N₆O₂ 425 16.8 88 801 2174 C₂₃H₂₄BrF₃N₄O₂S₂ 591 5.3 53 802 2178 C₂₅H₂₈F₃N₅O₄ 518 5.4 62 803 2179 C₂₅H₂₈F₃N₅O₃ 502 6.3 60

Example 804 Synthesis of (R)-1-(2-amino-4,5-methylenedioxybenzyl)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (Compd. No. 2127)

A mixture of (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-(4,5-methylenedioxy-2-nitrobenzyl)pyrrolidine (30.5 mg) with 10% Pd carbon (6 mg) and methanol (3 mL) was stirred at room temperature under a hydrogen atmosphere for 10 hours. The palladium catalyst was filtered through Celite, and the filtrate was concentrated and purified by solid-phase extraction (Bond Elut™ SI, 20% methanol/ethyl acetate) to thereby afford (R)-1-(2-amino-4,5-methylenedioxybenzyl)-3-[[N²-amino-5-trifluoromethylbenzoyl]glycyl]amino]pyrrolidine (Compd. No. 2127) (21.9 mg, 76%). The purity was determined by RPLC/MS (95%). ESI/MS m/e 480.1 (M⁺+H, C₂₂H₂₄F₃N₅O₄).

Examples 805 to 806

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 804. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 15.

TABLE 15 ESI/MS Yield Yield Example Compd. No. Molecular Formula m/e (mg) (%) 805 2128 C₂₂H₂₆F₃N₅O₃ 466.0 8.6 30 806 2129 C₂₂H₂₆F₃N₅O₂ 450.1 13.1 37

Example 807 Synthesis of (R)-1-(3-amino-4-chlorobenzyl)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (Compd. No. 2132)

A mixture of (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-(4-chloro-3-nitrobenzyl)pyrrolidine (32.6 mg) with 10% palladium carbon (8 mg), ethyl acetate (2.7 mL) and methanol (0.3 mL) was stirred at room temperature under a hydrogen atmosphere for 15 hours. The palladium carbon was removed by filtration, and the filtrate was concentrated and purified by solid-phase extraction (Bond Elut™ SI, 20% methanol/ethyl acetate) to thereby provide (R)-1-(3-amino-4-chlorobenzyl)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (Comp d. No. 2132) (10.5 mg, 34%). The purity was determined by RPLC/MS (84%). ESI/MS m/e 470.2 (M⁺+H, C₂₁H₂₃F₃N₅O₂).

Example 808 Synthesis of (R)-1-(2-amino-4,5-methylenedioxybenzyl)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine

A methanol (1.50 mL) solution of NaBH₃CN (0.75 mmol) was added to a mixture of (R)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (0.150 mmol) with 4,5-methylenedioxy-2-nitrobenzaldehyde (0.45 mmol), methanol (4.5 mL) and acetic acid (0.048 mL). The resulting reaction mixture was stirred at 50° C. overnight, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol. The obtained crude product was eluted with a 2 M methanol solution of NH₃ and concentrated to thereby afford (R)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]-1-(4,5-methylenedioxy-2-nitrobenzyl)pyrrolidine.

A mixture of the resulting (R)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl) glycyl]amino]-1-(4,5-methylenedioxy-2-nitrobenzyl)pyrrolidine (0.150 mmol) with 10% Pd carbon (22 mg) and methanol (4.5 mL) was stirred at room temperature under a hydrogen atmosphere overnight. The palladium catalyst was removed by filtration, and the filtrate was concentrated to thereby afford (R)-1-(2-amino-4,5-methylenedioxybenzyl)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (87.1 mg, quantitative). Any noticeable by-product was not detected in TLC.

Further, (R)-1-(3-amino-4-methoxybenzyl)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine and

(R)-1-(3-amino-4-methylbenzyl)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 808.

(R)-1-(3-amino-4-methoxybenzyl)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine: 101 mg, quantitative. Any noticeable by-product was not detected in TLC.

(R)-1-(3-amino-4-methylbenzyl)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine: 97.2 mg, quantitative. Any noticeable by-product was not detected in TLC.

Example 809 Synthesis of (R)-1-(3-amino-4-chlorobenzyl)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine

A methanol (1.50 mL) solution of NaBH₃CN (0.75 mmol) was added to a mixture of (R)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (0.150 mmol) with 4-chloro-3-nitrobenzaldehyde (0.45 mmol), methanol (4.5 mL) and acetic acid (0.048 mL). The resulting reaction mixture was then stirred at 50° C. overnight, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol. The obtained product was eluted with a 2 M methanol solution of NH₃ and concentrated to thereby provide (R)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]-1-(4-chloro-3-nitrobenzyl)pyrrolidine.

A mixture of the resulting (R)-3-[[N-(2-tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]-1-(4-chloro-3-nitrobenzyl)pyrrolidine with 10% Pd carbon (22 mg), ethyl acetate (2.7 mL) and methanol (0.3 mL) was stirred at room temperature under a hydrogen atmosphere for 15 hours. The palladium catalyst was removed by filtration, and the filtrate was concentrated to afford (R)-1-(3-amino-4-chlorobenzyl)-3-[[N-(2-tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (89.7 mg, quantitative). Any noticeable by-product was not detected in TLC.

Example 810 Synthesis of (R)-1-(3-amino-4-hydroxybenzyl)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (Compd. No. 2187)

A 4 M HCl dioxane (2.0 mL) solution of (R)-1-(3-amino-4-hydroxybenzyl)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (20 mg) synthesized according to the method of Example 808 was stirred at room temperature overnight. The solution was concentrated, and the residue was then dissolved in methanol, loaded onto a VarianM SCX column, washed with methanol, subsequently eluted with a 2 M methanol solution of NH₃, concentrated and then purified by preparative TLC (SiO₂, ethyl acetate/methanol=4:1) to thereby provide (R)-1-(3-amino-4-hydroxybenzyl)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (Compd. No. 2187) (9.6 mg, 59%). The purity was determined by RPLC/MS (86%). ESI/MS m/e 452.3 (M⁺+H, C₂₁H₂₄F₃N₅O₃).

Example 811 Synthesis of (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-[4-chloro-3-(dimethylamino)benzyl]pyrrolidine (Compd. No. 2133)

NaBH₃CN (38 mg) was added to a mixture of (R)-1-(3-amino-4-chlorobenzyl)-3-[[N-(2-tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl]glycyl]amino]pyrrolidine (44.9 mg) with methanol (0.95 mL), acetic acid (0.05 mL) and a 37% aqueous solution of HCHO (0.15 mL). The resulting reaction mixture was stirred at 50° C. overnight, cooled to room temperature and concentrated. A 2 M aqueous solution of NaOH and ethyl acetate were then added to the residue to separate the organic layer. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried and concentrated. The residue was loaded onto a Varian™ SCX column and washed with methanol. The resulting product was' eluted with a 2 M methanol solution of NH₃ and concentrated. The residue was dissolved in a 50% concentrated hydrochloric acid/dioxane and stirred at room temperature for 1 hour. The reaction solution was adjusted to pH 10 with a 5 M aqueous solution of NaOH and extracted with ethyl acetate (twice). The extracts were combined, dried over Na₂SO₄, filtered, concentrated and purified by preparative TLC (SiO₂, 20% methanol/ethyl acetate) to thereby afford (R)-3-[[N²-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-[4-chloro-3-(dimethylamino)benzyl]pyrrolidine (Compd. No. 2133) (10.9 mg, 28%). The purity was determined by RPLC/MS (95%). ESI/MS m/e 498.3 (M⁺+H, C₂₃H₂₇ClF₃N₅O₂).

Examples 812 to 814

The compounds used in the present invention were synthesized by using the respective starting materials and reactants according to the method of Example 811. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 16.

TABLE 16 ESI/MS Yield Yield Example Compd. No. Molecular Formula m/e (mg) (%) 812 2134 C₂₄H₂₈F₃N₅O₄ 508.4 19.0 50 813 2135 C₂₄H₃₀F₃N₅O₃ 494.4 21.8 50 814 2136 C₂₄H₃₀F₃N₅O₂ 478.4 29.2 69

Example 815 Synthesis of (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-(3-methylamino-4-hydroxybenzyl)pyrrolidine (Compd. No. 2158)

NaBH₃CN (9.2 mg) was added to a mixture of (R)-1-(3-amino-4-hydroxybenzyl)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (27.3 mg, 0.049 mmol) with a 37% HCHO solution (4.0 mg, 0.049 mmol), acetic acid (0.10 mL) and methanol (1.3 mL). The resulting reaction mixture was stirred at 60° C. overnight, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (8 mL) and concentrated.

The resulting residue was dissolved in methanol (1 mL), and a 4 M dioxane solution of HCl (1.0 mL) was added to the solution. The resulting mixture was stirred at room temperature for 3 hours and concentrated. The residue was dissolved in methanol (1 mL), loaded onto a Varian™ column, washed with methanol (5 mL×2), eluted with a 2 M methanol solution of NH₃ (8 mL), concentrated and then purified by preparative TLC (SiO₂) to thereby provide (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-(3-methylamino-4-hydroxybenzyl)pyrrolidine (Compd. No. 2158) (4.3 mg, 19%). The purity was determined by RPLC/MS (71%). ESI/MS m/e 480.3 (M⁺+H, C₂₂H₂₆F₃N₅O₃).

Example 816 Synthesis of (R)-1-(3-acetylamino-4-methoxybenzyl)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (Compd. No. 2152)

Acetic anhydride (1 mL) was added to a pyridine (1 mL) solution of (R)-1-(3-amino-4-hydroxybenzyl)-3-[[N-(2-(tert butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (50.5 mg). The resulting reaction mixture was stirred at room temperature overnight, and methanol was added to the mixture. The obtained mixture was concentrated, and a 1 M NaOH solution was then added to the concentrate. The resulting mixture was extracted with ethyl acetate, and the organic layer was concentrated and purified by preparative TLC (SiO₂) to thereby afford (R)-1-(3-acetylamino-4-methoxybenzyl)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine.

The resulting (R)-1-(3-acetylamino-4-methoxybenzyl)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine was dissolved in a 50% dioxane solution of 6 M hydrochloric acid, and the obtained solution was stirred at room temperature for 2 hours, adjusted to pH 10 with a 5 M NaOH solution and extracted with ethyl acetate. The organic layer was concentrated and purified by preparative TLC (SiO₂) to thereby provide (R)-1-(3-acetylamino-4-methoxybenzyl)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (Compd. No. 2152) (3.7 mg, 8%). The purity was determined by RPLC/MS (100%). ESI/MS m/e 508.3 (M⁺+H, C₂₄H₂₈F₃N₅O₄).

Examples 817 to 819

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 816. Data of ESI/MS, yields.(mg) and yields (%) are collectively shown in Table 17.

TABLE 17 ESI/MS Yield Yield Example Compd. No. Molecular Formula m/e (mg) (%) 817 2150 C₂₃H₂₅ClF₃N₅O₃ 512.3 3.8 9 818 2151 C₂₄H₂₆F₃N₅O₅ 522.2 3.1 8 819 2153 C₂₄H₂₈F₃N₅O₃ 492.3 4.3 10

Example 820 Synthesis of (R)-3-[[N(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-(benz[d]oxazol-5-yl)pyrrolidine (Compd. No. 2189)

Triethyl orthoformate (0.20 mL, 3.3 equivalents) and pyridinium p-toluenesulfonate (1.2 mg, 0.4 equivalent) were added to a THF (2 mL) solution of (R)-1-(3-amino-4-hydroxybenzyl)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]amino]pyrrolidine (20 mg) synthesized according to the method of Example 808. The resulting reaction mixture was stirred at room temperature overnight under reflux. The reaction mixture was cooled to room temperature and then concentrated. The obtained residue was dissolved in ethyl acetate, loaded onto a Bond Elut™ Si column, eluted with ethyl acetate/methanol=4:1 and concentrated.

The resulting residue was dissolved in ethyl acetate (1.5 mL), and a 4 M dioxane solution of HCl was added to the obtained solution. The resulting solution was stirred overnight, adjusted to pH 10 with a 5 M aqueous solution of NaOH and extracted with ethyl acetate. The obtained extract was concentrated and purified by preparative TLC (SiO₂, ethyl acetate/methanol=4:1) to thereby provide (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-(benz[d]oxazol-5-yl)pyrrolidine (Comp d. No. 2189) (0.5 mg, 3%). The purity was determined by RPLC/MS (97%). ESI/MS m/e 462.3 (M⁺+H, C₂₂H₂₂F₃N₅O₃).

Example 821 Synthesis of (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-[benzo[c]thiadiazol-5-yl]pyrrolidine (Compd. No. 2183)

Methanesulfonyl chloride (0.0042 mL) was added to a mixture of 5-(hydroxymethyl)benzo[c]thiadiazole (8.3 mg, 0.050 mmol) with a (piperidinomethyl)polystyrene (86 mg) and chloroform (1 mL). The resulting mixture was stirred at room temperature for 1.5 hours. Acetonitrile (1 ml) and (R)-3-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzyl)glycyl]amino]pyrrolidine (0.060 mmol) were added to the mixture. The resulting mixture was stirred at 50° C. for 3 hours. After cooling to room temperature, phenyl isocyanate (30 mg) was added, and the obtained mixture was stirred at room temperature for 1 hour, loaded onto a Varian™ SCX column and washed with methanol (5 mL) and chloroform (5 mL). The resulting crude product was eluted with a 2 M methanol solution of NH₃ (3 mL) and concentrated.

The obtained substance was dissolved in dichloromethane (1 mL), and a dichloromethane solution (1 mL) of 1 M chlorotrimethylsilane (1 M) and phenol (1 M) was added to the solution. The resulting solution was stirred at room temperature for 5 hours, loaded onto a Varian™ SCX column and washed with methanol and dichloromethane. The obtained product was eluted with a 2 M methanol solution of NH₃ and concentrated.

The resulting crude product was purified by preparative TLC (SiO₂, ethyl acetate/methanol=3:1) to thereby afford (R)-3-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]amino]-1-[benzo[c]thiadiazol-5-yl]pyrrolidine (Compd. No. 2183) (11.5 mg, 58%). The purity was determined by RPLC/MS (86%). ESI/MS m/e 479.2 (M⁺+H, C₂₁H₂₁F₃N₆O₂S).

Reference Example 6 Synthesis of 4-[[N-(1-(9-fluorenylmethoxycarbonyl)pyrrolidin-3-yl)carbamoylmethyl]aminomethyl]3-methoxyphenyloxymethyl-polystyrene

Acetic acid (0.3 mL), sodium triacetoxyborohydride (1.92 g) and a 4-formyl-3-(methoxyphenyloxymethyl)-polystyrene (1 mmol/g, 200 g) were added to a DMF (65 mL) solution of (R)-1-(9-fluorenylmethoxycarbonyl)-3-glycylaminopyrrolidine hydrochloride (4.38 g, 10 mmol). The resulting mixture was shaken for 2 hours and then filtered. The resin was washed with methanol, DMF, dichloromethane and methanol and dried to thereby provide the objective substance (2.73 g).

Examples 822 to 912 Solid-phase synthesis of 3-aminopyrrolidines

Disopropylethylamine (3.6 mL) was added to a mixture of the corresponding carboxylic acid (1.6 mmol) with HBTU (1.6 mmol) and DMF (6 mL), and the resulting mixture was shaken for 2 minutes. A 4-[[N-(1-(9-fluorenylmethoxycarbonyl)pyrrolidin-3-yl)carbamoylmethyl]aminomethyl]-3-methoxyphenyloxymethyl-polystyrene (400 mg, 0.4 mmol) was added, and the obtained mixture was shaken for 1 hour and then filtered. The resin was washed with DMF and dichloromethane and dried.

A mixture of the resulting resin with piperidine (3.2 mL) and DMF (12.8 mL) was shaken for 10 minutes and then filtered. The resin was washed with DMF and dichloromethane and dried.

A mixture of NaBH(OAc)₃ (0.25 mmol) with acetic acid (0.025 mL) and DMF (1 mL) was added to the dried resin (0.05 mL). The corresponding aldehyde (2.5 mmol) was added, and the mixture was shaken for 2 hours, then filtered and washed with methanol, a 10% solution of diisopropylethylamine in DMF, DMF, dichloromethane and methanol. A mixture of the resin with water (0.050 mL) and trifluoroacetic acid (0.95 mL) was shaken for 1 hour and then filtered. The resin was washed with dichloromethane and methanol. The filtrate and washings were combined and concentrated. The resulting crude product was loaded onto a Varian™ SCX column and washed with methanol (15 mL). The product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated.

The obtained products, if necessary, were purified with preparative TLC or HPLC to thereby afford the objective compounds. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 18.

TABLE 18 ESI/MS Yield Yield Example Compd. No. Molecular Formula m/e (mg) (%) 822 1805 C₂₁H₂₁BrF₃N₃O₂S 516 13.3 76 823 1806 C₂₂H₂₄F₃N₃O₃S 468 12.8 81 824 1807 C₂₂H₂₄F₃N₃O₄S 484 13.7 83 825 1808 C₂₂H₂₄F₃N₃O₄S 484 14.9 91 826 1809 C₂₁H₂₂F₃N₃O₃S 454 12.9 84 827 1810 C₂₂H₂₂F₃N₃O₄S 482 12.9 79 828 1811 C₂₄H₂₆F₃N₃O₂S 478 12.9 79 829 1812 C₂₂H₂₄F₃N₃O₂S₂ 484 5.3 32 830 1813 C₂₃H₂₆F₃N₃O₂S 466 12.8 81 831 1814 C₂₃H₂₄F₃N₃O₃S 480 9.7 59 832 1815 C₂₃H₂₆F₃N₃O₂S 466 12.7 80 833 1816 C₂₄H₂₈F₃N₃O₂S 480 14.4 88 834 1817 C₂₅H₃₀F₃N₃O₂S 494 14.1 84 835 1818 C₂₁H₂₂BrF₂N₃O₃ 482 13.4 82 836 1819 C₂₂H₂₅F₂N₃O₄ 434 11.7 79 837 1820 C₂₂H₂₅F₂N₃O₅ 450 11.8 77 838 1821 C₂₂H₂₅F₂N₃O₅ 450 13.3 87 839 1822 C₂₁H₂₃F₂N₃O₄ 420 11.9 83 840 1823 C₂₂H₂₃F₂N₃O₅ 448 11.9 78 841 1824 C₂₄H₂₇F₂N₃O₃ 444 9.1 60 842 1825 C₂₂H₂₅F₂N₃O₃S 450 11.3 74 843 1826 C₂₃H₂₇F₂N₃O₃ 432 10.8 74 844 1827 C₂₃H₂₅F₂N₃O₄ 446 12.7 84 845 1828 C₂₃H₂₇F₂N₃O₃ 432 11.7 80 846 1829 C₂₄H₂₉F₂N₃O₃ 446 14.3 94 847 1830 C₂₄H₂₉F₂N₃O₃ 446 10.0 66 848 1831 C₂₂H₂₈BrN₃O₃ 462 4.8 31 849 1832 C₂₃H₃₁N₃O₄ 414 10.4 74 850 1833 C₂₃H₃₁N₃O₅ 430 12.1 83 851 1834 C₂₃H₃₁N₃O₅ 430 12.0 82 852 1835 C₂₂H₂₉N₃O₄ 400 7.9 58 853 1836 C₂₃H₂₉N₃O₅ 428 11.1 76 854 1837 C₂₅H₃₃N₃O₃ 424 13.3 92 855 1838 C₂₃H₃₁N₃O₃S 430 8.7 60 856 1839 C₂₄H₃₃N₃O₃ 412 11.3 81 857 1840 C₂₄H₃₁N₃O₄ 426 12.9 89 858 1841 C₂₄H₃₃N₃O₃ 413 12.8 91 859 1842 C₂₅H₃₅N₃O₃ 426 8.7 60 860 1843 C₂₅H₃₅N₃O₃ 426 12.2 84 861 1844 C₂₆H₃₇N₃O₃ 440 11.3 76 862 1845 C₃₁H₃₇BrN₄O₂ 577 6.4 30 863 1846 C₂₃H₂₈F₃N₃O₂S 480 12.8 81 864 1847 C₂₅H₃₁F₂N₃O₃ 460 12.2 78 865 1848 C₂₇H₂₉N₃O₄ 460 6.1 39 866 1849 C₂₉H₃₁N₃O₂ 454 15.1 98 867 1850 C₂₈H₃₁N₃O₂ 442 12.7 85 868 1851 C₂₈H₃₁N₃O₂ 442 14.3 95 869 1852 C₂₈H₂₉N₃O₃ 456 3.4 22 870 1853 C₂₇H₂₉N₃O₆S 524 15.4 87 871 1854 C₂₉H₃₁N₃O₄S 518 15.8 90 872 1855 C₂₈H₃₁N₃O₄S 506 17.0 99 873 1856 C₂₈H₃₁N₃O₄S 506 3.0 17 874 1857 C₂₈H₂₉N₃O₅S 520 10.0 57 875 1858 C₂₀H₂₂Br₂N₄O₂ 511 9.3* 37 876 1859 C₂₁H₂₅BrN₄O₃ 461 6.7* 29 877 1860 C₂₁H₂₅BrN₄O₄ 477 9.5* 40 878 1861 C₂₁H₂₅BrN₄O₄ 477 10.0* 42 879 1862 C₂₀H₂₃BrN₄O₃ 447 7.8* 34 880 1863 C₂₁H₂₃BrN₄O₄ 475 3.4* 14 881 1864 C₂₁H₂₅BrN₄O₂S 477 3.9* 16 882 1865 C₂₂H₂₅BrN₄O₃ 473 6.4* 27 883 1866 C₂₃H₂₉BrN₄O₂ 472 7.0* 29 884 1867 C₂₃H₂₉BrN₄O₂ 473 7.6* 32 885 1868 C₂₄H₃₁BrN₄O₂ 487 9.1* 37 886 1869 C₂₀H₂₂BrIN₄O₂ 557 8.9* 33 887 1870 C₂₁H₂₅IN₄O₃ 509 9.2* 37 888 1871 C₂₁H₂₅IN₄O₄ 525 6.3* 25 889 1872 C₂₁H₂₅IN₄O₄ 525 5.9* 23 890 1873 C₂₀H₂₃IN₄O₃ 495 7.7* 31 891 1874 C₂₁H₂₃IN₄O₄ 523 8.2* 32 892 1875 C₂₃H₂₇IN₄O₂ 519 6.7* 26 893 1876 C₂₁H₂₅IN₄O₂ 525 4.3* 17 894 1877 C₂₂H₂₇IN₄O₂ 507 7.9* 32 895 1878 C₂₂H₂₅IN₄O₃ 521 8.4* 33 896 1879 C₂₃H₂₉IN₄O₂ 521 8.2* 32 897 1880 C₂₃H₂₉IN₄O₂ 521 8.1* 32 898 1881 C₂₄H₃₁IN₄O₂ 535 8.6* 33 899 1882 C₂₀H₂₂BrN₅O₄ 476 5.3* 22 900 1883 C₂₁H₂₅N₅O₅ 428 5.7* 26 901 1884 C₂₁H₂₈N₅O₆ 444 8.2* 36 902 1885 C₂₁H₂₅N₅O₆ 444 5.0* 22 903 1886 C₂₀H₂₃N₅O₅ 414 8.7* 40 904 1887 C₂₁H₂₃N₅O₆ 442 7.8* 34 905 1888 C₂₃H₂₇N₅O₄ 438 5.6* 25 906 1889 C₂₁H₂₅N₅O₄S 444 13.2* 58 907 1890 C₂₂H₂₇N₅O₄ 426 11.3* 51 908 1891 C₂₂H₂₅N₅O₅ 440 7.4* 33 909 1892 C₂₂H₂₇N₅O₄ 426 5.5* 25 910 1893 C₂₃H₂₉N₅O₄ 440 5.7* 25 911 1894 C₂₃H₂₉N₅O₄ 440 9.4* 41 912 1895 C₂₄H₃₁N₅O₄ 455 8.5* 37 Note: *indicates “yield (mg) of trifluoroacetate”.

Reference Example 7 Synthesis of 2-carbamoyl-1-(4-chlorobenzyl)pyrrolidine

Triethylamine (7.45 mL) and 4-chlorobenzyl chloride (3.88 g, 24.1 mmol) were added to an acetonitrile (35 mL) solution of dl-prolinamide hydrochloride (2.5 g, 21.8 mmol). The resulting reaction mixture was stirred at 70° C. for 4 hours and subsequently stirred at 25° C. for 16 hours. The resulting mixture was diluted with dichloromethane (20 mL) and washed with water (30 mL×3). The organic layer was dried (over MgSO₄) and concentrated. The obtained crude product was purified by chromatography (SiO₂, methanol-dichloromethane) to thereby provide 2-carbamoyl-1-(4-chlorobenzyl)pyrrolidine (5.21 g, 81%).

Reference Example 8 Synthesis of 2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine

2-Carbamoyl-1-(4-chlorobenzyl)pyrrolidine was dissolved in 1 M BH₃-THF (9.4 mL), and the resulting solution was heated at 70° C. A 1 M BH₃-THF (0.5 equivalent) was further added twice after 16 hours and 25 hours. After 40 hours, a 1 M hydrochloric acid was added, and the resulting mixture was refluxed for 3 hours. A 3 M hydrochloric acid (6 mL) was added, and the reaction product was stirred for another 3 hours with heating, then cooled to 25° C., alkalinized with a 6 M aqueous solution of NaOH and extracted with dichloromethane (4×15 mL). The obtained crude product was purified by chromatography (SiO₂, PrOH/H₂O/NH₄OH=8:1:1) to thereby afford 2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (1.21 g, 86%).

Furthermore, optically active (S)-2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine and (R)-2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine were synthesized by using the respective corresponding starting materials and reactants according to the above method.

(S)-2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine: ¹H NMR (CDCl₃, 400 MHz) δ 1.40-1.80 (m, 5H), 1.80-1.95 (m, 1H), 2.12-2.21 (m, 1H), 2.48-2.65 (m, 1H), 2.66-2.78 (m, 2H), 2.85-2.95 (m, 1H), 3.26 (d, J=13.2 Hz, 1H), 3.93 (d, J=13.2, 1H), 7.20-7.40 (m, 4H).

(R)-2-(Aminomethyl)-1-(4-chlorobenzyl)pyrrolidine exhibited the same ¹H NMR as that of the (S)-isomer.

Example 913 Synthesis of 2-[[N(benzoylleucyl)aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compd. No. 344)

EDCl (23 mg), HOBt (16.2 mg) and triethylamine (15.2 μL) were added to a chloroform (1 mL) solution of 2-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (22.5 mg, 0.10 mmol) and dl-benzoylleucine (0.12 mL), and the resulting mixture was stirred at 25° C. for 16 hours. The reaction mixture was diluted with dichloromethane (0.5 mL), washed with a 2 M aqueous solution of NaOH (0.75 mL×2), filtered through a PTFE membrane, thereby dried and concentrated to provide 2-[(N-benzoylleucyl)aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compd. No. 344) (74 mg, quantitative). The purity was determined by RPLC/MS (85%). ESI/MS m/e 442 (M⁺+H, C₂₃H₃₂ClN₃O₂).

Examples 914 to 933

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 913. The obtained products, if necessary, were purified by chromatography (HPLC-C₁₈, acetonitrile/H₂O/TFA), and the objective compounds were obtained as TFA salts. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 19. Compd. Nos. 339 and 340 exhibited the following ¹H NMR, respectively.

TABLE 19 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 914 330 C₂₁H₂₄ClN₃O₂ 386  75* Q 915 331 C₂₂H₂₆Cl₃O₂ 400  44* 70 916 332 C₂₄H₃₀ClN₃O₅ 476 57 Q 917 333 C₂₀H₂₃ClN₄O₂ 387 40 Q 918 334 C₂₂H₂₆ClN₃O₂ 400 68 Q 919 335 C₂₁H₂₃ClN₄O₄ 431 73 Q 920 336 C₂₂H₂₃ClF₃N₃O₂ 454 75 Q 921 337 C₂₂H₂₆ClN₃O₂ 400 68 Q 922 338 C₂₂H₂₆ClN₃O₂ 400 70 Q 923 341 C₂₂H₂₆ClN₃O₂ 400  80* Q 924 342 C₂₂H₂₆ClN₃O₂ 400 68 Q 925 343 C₂₄H₃₀ClN₃O₂ 428 63 Q 926 345 C₂₃H₂₇ClN₂O₂ 399  68* Q 927 346 C₂₃H₂₆ClFN₂O₃ 433 51 Q 928 347 C₂₄H₂₉ClN₂O₂ 413 47 Q 929 348 C₂₃H₂₇ClN₂O₂ 399 26 Q 930 349 C₂₁H₂₅ClN₂O₃S 421 42 Q 931 350 C₂₆H₃₃ClN₂O₃ 457   12.4 54 932 351 C₂₂H₂₆ClN₃O₃ 416 34 81 933 352 C₂₂H₂₅Cl₂N₃O₃ 450 51 Q Notes *indicates “yield (mg) of trifluoroacetate”. Q means “Quantitative”.

Example 934

Compd. No. 339: 82%; ¹H NMR (CDCl₃) δ 1.52-1.75 (m, 4 H), 1.84-1.95 (m, 1H), 2.10-2.20 (m, 1H), 2.67-2.78 (m, 1H), 2.80-2.90 (m, 1H), 3.10-3.20 (m, 1H), 3.25 (d, J=13.1 Hz, 1H), 3.50-3.60 (m, 1H), 3.89 (d, J=13.1 Hz, 1H), 4.28-4.20 (m, 2H), 7.00-7.05 (m, 1H), 7.12-7.29 (m, 4H), 7.51 (t, J=7.8 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 8.10-8.27 (m, 2H).

Example 935

Compd. No. 340: 68%; ¹H NMR (CDCl₃) δ 1.55-1.73 (m, 4H), 1.86-1.97 (m, 1H), 2.12-2.21 (m, 1H), 2.67-2.76 (m, 1H), 2.86-2.93 (m, 1H), 3.14-3.21 (m, 1H), 3.27 (d, J=13.1 Hz, 1H), 3.52-3.59 (m, 1H), 3.89 (d, J=13.1 Hz, 1H), 4.09-4.21 (m, 2H), 7.00-7.07 (m, 1H), 7.12-7.30 (m, 4H), 7.50 (t, J=7.8 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 8.10-8.25 (m, 2H).

Reference Example 9 Synthesis of 3-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine

A 0.5 M dioxane solution of ammonia (60 mL, 30 mmol) was added to a mixture of 4-carboxy-1-(4-chlorobenzyl)pyrrolidin-2-one (5.05 g, 20 mmol) with EDCI (2.85 g, 22 mmol), HOBt (2.97 g, 22 mmol) and dichloromethane (100 mL). The resulting reaction mixture was stirred at room temperature for 15 hours and washed with 2 M HCl (three times) and a 2 M aqueous solution of NaOH (100 mL×4). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to thereby provide 4-carbamoyl-(4-chlorobenzyl)pyrrolidin-2-one (1.49 g) as a colorless solid.

A 1.0 M THF solution of BH₃ (25 mL) was added to a THF (15 mL) solution of 4-carbamoyl-1-(4-chlorobenzyl)pyrrolidin-2-one (1.49 g). The resulting reaction mixture was stirred for 15 hours and cooled to room temperature. The solvent was then removed under reduced pressure. Water (30 mL) and concentrated hydrochloric acid (10 mL) were added, and the mixture was stirred at 100° C. for 2 hours and at room temperature for 1 hour. A 2 M aqueous solution of NaOH (100 mL) was added, and the obtained mixture was extracted with ethyl acetate (50 mL×3). The organic layers were combined, dried over K₂CO₃, filtered, concentrated and purified by column chromatography (SiO₂, 15% methanol-5% triethylamine/dichloromethane) to thereby afford 3-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (860 mg, 19%) as a colorless oil.

Reference Example 10 Synthesis of 1-(4-chlorobenzyl)-3-[(glycylamino)methyl]pyrrolidine

A mixture of 3-(aminomethyl)-1-(4-chlorobenzyl)pyrrolidine (860 mg, 3.8 mmol) with triethylamine (5.7 mmol), N-tert-butoxycarbonylglycine (704 mg), EDCI (594 mg), HOBt (673 mg) and dichloromethane (20 mL) was stirred at room temperature for 15 hours, and dichloromethane (50 mL) was added to the mixture. The resulting solution was washed with a 2 M aqueous solution of NaOH (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated to thereby provide 3-[[N-(tert-butoxycarbonyl)glycl]aminomethyl]-1,1-(4-chlorobenzyl)pyrrolidine (1.31 g, 90%).

A 4 M dioxane solution of HCl (5 mL) was added to a methanol (10 mL) solution of 3-[[N-tert-butoxycarbonyl)glycyl]aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (804 mg, 2.11 mmol). The resulting solution was stirred at room temperature for 3.5 hours and then concentrated, and a 1 M aqueous solution of NaOH (20 mL) was added. The resulting mixture was extracted with dichloromethane (20 mL×3), and the extracts were combined, dried over sodium sulfate and concentrated to thereby afford 1-(4-chlorobenzyl)-3-[(glycylamino)methyl]pyrrolidione (599 mg, 100%). The purity was determined by RPLC/MS (100%). ESI/MS m/e 282.2 (M⁺+H, C₁₄H₂₀ClN₃O).

Example 936 Synthesis of 3-[[N-[3-trifluoromethylbenzoyl]glycyl]aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compd. No. 1463)

A dichloromethane (0.2 mL) solution of 3-(trifluoromethyl)benzoyl chloride (0.058 mmol) was added to a mixture of a chloroform (0.2 m-L) solution of 1-(4-chlorobenzyl)-3-[(glycylamino)methyl]pyrrolidine (0.050 mmol) with a dichloromethane (1 mL) solution of a piperidinomethylpolystyrene (60 mg). The resulting reaction mixture was stirred at room temperature for 2.5 hours, and methanol (0.30 mL) was then added. The reaction mixture was loaded onto a Varian™ SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a methanol (5 mL) solution of 2 M NH₃ and concentrated to thereby provide 3-[[N-[3-trifluoromethylbenzoyl]glycyl]aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compd. No. 1463) (22.4 mg, 99%). The purity was determined by RPLC/MS (97%). ESI/MS m/e 454.2 (M⁺+H, C₂₂H₂₃ClF₃N₃O₂).

Examples 937 to 944

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 936. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 20.

TABLE 20 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 937 1464 C₂₂H₂₃ClF₃N₃O₃ 470.0 21.0 89 938 1465 C₂₃H₂₂ClF₆N₃O₂ 522.0 24.5 94 939 1466 C₂₁H₂₃BrClN₃O₂ 466.0 20.8 90 940 1467 C₂₁H₂₃Cl₂N₃O₂ 420.0 19.6 93 941 1468 C₂₁H₂₃ClN₄O₄ 431.2 19.5 91 942 1469 C₂₂H₂₂ClF₄N₃O₂ 472.0 21.8 92 943 1470 C₂₁H₂₂Cl₃N₃O₂ 456.0 22.1 97 944 1471 C₂₁H₂₂ClF₂N₃O₂ 422.0 20.9 99

Example 945 Synthesis of 3-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compd. No. 1506)

2-Amino-4,5-difluorobenzoic acid (0.060 mmol), diisopropylcarbodiimide (0.060 mmol) and HOBt (0.060 mmol) were added to a solution of 1-(4-chlorobenzyl)-3-[(glycylamino)methyl]pyrrolidine (0.050 mmol) in chloro form (1.35 mL) and tert-butanol (0.05 mL). The resulting reaction Mixture was stirred at room temperature for 19 hours, then loaded onto a Varian™ SCX column and washed with methanol/chloroform=1:1 (10 mL) and methanol (10 mL). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated to thereby afford 3-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compd. No. 1506) (22.0 mg, quantitative). The purity was determined by RPLC/MS (92%). ESI/MS m/e 437 (M⁺+H, C₂₁H₂₃ClF₂N₄O₂).

Examples 946 to 952

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 945. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 21.

TABLE 21 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 946 1506 C₂₁ ₂₄BrClN₄O₂ 481 20.6 86 947 1507 C₂₁H₂₄FClN₄O₂ 419 21.7 Q 948 1509 C₂₇H₂₈ClN₃O₂ 462 26.5 Q 949 1510 C₂₁H₂₄ClIN₄O₂ 527 22.0 84 950 1511 C₁₉H₂₁BrClN₃O₂S 472 23.7 Q 951 1512 C₂₁H₂₄Cl₂N₄O₂ 435 22.3 Q 952 1513 C₂₇H₂₈ClN₃O₄S 526 24.6 94 Note: Q means “Quantitative”.

Reference Example 11 Synthesis of 1-(4-chlorobenzyl)nipecotic acid

4-Chlorobenzyl chloride (6.42 g, 39.9 mmol) and ^(i)Pr₂NEt (7.74 g, 40.0 mmol) were added to an acetonitrile (15 mL) solution of ethyl nipecotate (6.29 g, 40.0 mmol). The resulting reaction mixture was stirred at 70° C. for 1.5 hours, and the solvent was removed under reduced pressure. A saturated aqueous solution of NaHCO₃ (50 mL) was added to the residue, and the resulting mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with a saturated aqueous solution of NaHCO₃ and dried over Na₂SO₄. The solvent was removed under reduced pressure to thereby provide ethyl 1-(4-chlorobenzyl)nipecotate as a reddish yellow oil. (11.0 g, 97.8%). The resulting oil was used without purification. The purity was determined by RPLC/MS (97%). ESI/MS m/e 382.2 (M⁺+H, C₁₅H₂₁ClNO₂).

An H₂O (25 mL) solution of LiOH (1.66 g) was added to a THF (60 mL) solution of ethyl 1-(4-chlorobenzyl)nipecotate. The resulting reaction mixture was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure to provide an amorphous solid. The obtained crude product was purified by column chromatography (SiO₂, 50% methanol-dichloromethane) to afford 1-(4-chlorobenzyl)nipecotic acid (9.75 g, 98.2%) as an off-while amorphous solid. The purity was determined by RPLC/MS (>95%). ESI/MS m/e 254.0 (M⁺+H, C₁₃H₁₇ClNO₂).

Reference Example 12 Synthesis of 1-(4-chlorobenzyl-3-[(tert-butoxcyarbonyl)amino]piperidine

Triethylamine (3.38 g) and activated 3 Å molecular sieve (30 g) were added to a ^(t)BuOH (500 mL) solution of 1-(4-chlorobenzyl)nipecotic acid (7.06 g, 27.8 mmol). Diphenylphosphoryl azide (8.58 g) was added, and the resulting reaction mixture was stirred under reflux for 18 hour and cooled. The solvent was removed under reduced pressure. The obtained residue was then dissolved in ethyl acetate (500 mL), and the organic layer was washed with a saturated aqueous solution of NaHCO₃ (100 mL×2) and brine (50 mL), then dried (over Na₂SO₄) and concentrated under reduced pressure. The obtained crude product was purified by chromatography (SiO₂, 25% ethyl acetate-hexane) to provide 1-(4-chlorobenzyl-3-[(tert-butoxycarbonyl)amino]piperidine (2.95 g, 32.6%) as a white crystalline solid. ¹H NMR (CDCl₃, 300 MHz) δ 1.4-1.75 (br, 4H), 2.2-2.7 (br, 4H), 3.5 (br, 2H), 3.8 (br, 4H), 7.3 (br, 4H). The purity was determined by RPLC/MS (>99%). ESI/MS m/e 269.2 (M⁺+H-56, C₁₇H₂₆ClN₂O₂).

Reference Example 13 Synthesis of 3-amino-1-(4-chlorobenzyl)piperidine

To a methanol (25 mL) solution of 1-(4-chlorobenzyl)-3-[(tert-butoxycarbonyl)amino]piperidine (2.55 g, 7.85 mmol), was added 1M HCl-Et₂O (50 mL). The resulting reaction mixture was stirred at 25° C. for 15 hours, and the solvent was removed under reduced pressure to afford 3-amino 1-(4-chlorobenzyl)piperidine dihydrochloride as an amorphous solid (2.49 g, quantitative). The purity was determined by RPLC/MS (>95%). ESI/MS m/e 225.2 (M⁺+H, C₁₂H₁₈ClN₂).

Example 953 Synthesis of 1-(4-chlorobenzyl)-3-[[N-(3-methylbenzoyl)glycyl]amino]piperidine (Compd. No. 355)

N-(3-Methylbenzoyl)glycine (10.6 mg, 0.055 mmol), EDCI (10.5 mg) and 1-hydroxybenzotriazole hydrate (7.4 g) were added to a chloroform (2.5 mL) solution of 1-(4-chlorobenzyl)-3-aminopiperidine dihydrochloride (1.49 mg, 0.050 mmol) and triethylamine (15.2 mg). The resulting reaction mixture was stirred at 25° C. for 16 hours and washed with a 2 N aqueous solution of NaOH (2 mL×2) and brine (1 mL). After filtration through a PTFE membrane, the solvent was removed under reduced pressure to provide 1-(4-chlorobenzyl)-3-[[N-(3-methylbenzoyl)glycyl]amino]piperidine (Compd. No. 355) (17.4 mg, 87%). The purity was determined by RPLC/MS (97%). ESI/MS m/e 400.0 (M⁺+H, C₂₂H₂₆ClN₃O₂).

Examples 954 to 982

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 953. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 22. The Compd. No. 358 exhibited the following ¹H NMR.

TABLE 22 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 954 354 C₂₁H₂₄ClN₃O₂ 386 16.1 83 955 356 C₂₀H₂₃ClN₄O₂ 387 19.4 100  956 357 C₂₂H₂₆ClN₃O₂ 400 16.8 84 957 359 C₂₂H₂₆ClN₃O₂ 400 8.9 17 958 360 C₂₂H₂₅ClN₄O₄ 445 25.6 Q 959 361 C₂₃H₂₇ClN₂O₂ 399 15.5 29 960 362 C₂₄H₂₉ClN₂O₃ 429 12.4 58 961 363 C₂₁H₂₅ClN₂O₂S 405 22.2 Q 962 364 C₂₄H₂₉ClN₂O₄ 445 20.7 93 963 365 C₂₄H₂₉ClN₂O₂ 413 15.6 75 964 366 C₂₃H₂₆ClFN₂O₃ 433 21.6 100  965 367 C₂₃H₂₇ClN₂O₂ 399 11.9 60 966 368 C₂₂H₂₅ClN₂O₂ 385 16.0 83 967 369 C₂₂H₂₄Cl₂N₂O₂ 419 13.9 60 968 370 C₂₆H₃₃ClN₂O₃ 457 15.9 54 969 371 C₂₅H₃₁ClN₂O₃ 443 19.6 84 970 372 C₂₁H₂₅ClN₂O₃S 421 23.0 Q 971 373 C₂₃H₂₈ClN₃O₂ 414 19.1 92 972 374 C₂₄H₃₀ClN₃O₃ 444 18.6 84 973 375 C₂₃H₂₇Cl₂N₃O₂ 448 18.0 80 974 376 C₂₄H₃₀ClN₃O₃ 444 19.6 88 975 377 C₂₅H₃₁Cl₂N₃O₂ 476 20.7 87 976 378 C₂₇H₃₃ClFN₃O₂ 486 23.9 98 977 379 C₂₅H₃₀ClN₃O₃ 456 33.3 Q 978 380 C₂₄H₃₀ClN₃O₂ 428 9.8 46 979 381 C₂₁H₂₆ClN₃O₃S 436 10.3 47 980 382 C₂₂H₂₆ClN₃O₃ 416 24.4 Q 981 383 C₂₂H₂₅Cl₂N₃O₃ 450 27.5 Q Note: Q means “Quantitative”.

Example 982

Compd. No. 358: 88%; ¹H NMR (CDCl₃) δ 1.53-1.75 (m, 4 H), 2.12-2.20 (m, 1H), 2.37-2.50 (m, 2H), 2.53-2.61 (m, 1H), 3.38-3.50 (m, 2H), 2.53-2.61 (m, 1H), 3.38-3.50 (m, 2H), 4.06-4.20 (m, 3H), 7.10-7.13 (m, 1H), 7.18-7.30 (m, 4H), 7.59 (t, J=7.8 Hz, 1H), 7.79 (d, J=7.8 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 8.11 (s, 1H).

Reference Example 14 Synthesis of 1-benzyl-4-[[N-(tert-butoxycarbonyl)glycyl]amino]piperidine

N-(tert-Butoxycarbonyl)glycine (3.48 g, 20 mmol), EDCI (4.02 g, 21 mmol) and HOBt (2.83 g, 21 mmol) were added to a dichloromethane (40 mL) solution of 4- amino-1-benzylpiperidine (3.80 g, 20 mmol). The resulting reaction mixture was stirred at room temperature for 12 hours, and a 2 M solution of NaOH was then added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL×2). The organic layers were combined, washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by column chromatography (SiO₂, ethyl acetate/methanol/triethylamine=85:12:3) to afford 1-benzyl-4-[[N-(tert-butoxycarbonyl)glycyl]amino]piperidine (6.59 g, 95%).

Reference Example 15 Synthesis of 1-benzyl-4-(glycylamino)piperidine

A 4 M dioxane solution of HCl was added to a methanol (80 mL) solution of 1-benzyl-4-[N-(tert-butoxycarbonyl)glycyl]aminopiperidine (6.59 g). The resulting solution was stirred at room temperature for 2 hours and concentrated. A 2 M aqueous solution of NaOH (20 mL) was then added to the solution. The resulting mixture was extracted with dichloromethane (40 mL). The extracts were combined, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by column chromatography (SiO₂, ethyl acetate/methanol/triethylamine=85:12:3) to thereby provide 1-benzyl-4-(glycylamino)piperidine (3.91 g, 83%). ¹H NMR (CDCl₃, 400 MHz) δ 1.47-1.59 (m, 2H), 1.59 (br, 2H), 1.76-1.96 (m, 2H), 2.10-2.19 (m, 2H), 2.75-2.87 (m, 2H), 3.29 (s, 2H), 3.50 (s, 2H), 3.65-3.89 (m, 1H), 7.15-7.23 (m, 1H), 7.23-7.33 (m, 5H).

Other 4-acylamino-1-benzylpiperidines were synthesized by using the respective corresponding starting materials and reactants according to the methods of Reference Examples 14 and 15.

4-(β-alanylamino)-1-benzylpiperidine: 2.46 g, 51% (two steps)

1-benzyl-4-((S)-leucylamino)piperidine: 1.78 g, 74% (two steps) and 1-benzy-4-((R)-leucylamine)piperidine: 1.48 g, 61% (two steps).

Example 983 Synthesis of 4-(N-benzoylglycyl)amino-1-benzylpiperidine (Compd. No. 386)

A chloroform (0.4 mL) solution of benzoyl chloride (0.060 mmol) was added to a chloroform (1.0 mL) solution of 1-benzyl-4-(glycylamino)piperidine (0.050 mmol) and triethylamine (0.070 mmol). The resulting reaction mixture was shaken at room temperature for 12 hours, and an (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was added to the mixture. The obtained mixture was shaken at room temperature for 12 hours. The resulting reaction mixture was filtered, and the resin was washed with dichloromethane (0.5 mL). The filtrate and washings were combined, and dichloromethane (4 mL) was added. The solution was washed with a 2 M aqueous solution of NaOH (0.5 mL) to provide 4-(N-benzoylglycyl)amino-1-benzylpiperidine (Compd. No. 386) (11.3 mg, 64%). The purity was determined by RPLC/MS (94%). ESI/MS m/e 352.0 (M⁺+H, C₂₁H₂₅N₃O₂).

Examples 984 to 1034

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 983. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 23.

TABLE 23 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 984 384 C₂₂H₂₆ClN₃O₂ 400 60.0 Q 985 385 C₂₁H₂₃ClN₄O₄ 431 58.7 91 986 387 C₂₅H₂₇N₃O₂ 402.5 15.5 77 987 388 C₂₁H₂₄N₄O₄ 397.0 16.2 82 988 389 C₂₃H₂₇N₃O₄ 410.0 16.2 79 989 390 C₂₂H₂₄F₃N₃O₂ 420.0 17.4 83 990 391 C₂₂H₂₃F₄N₃O₂ 438.0 18.4 84 991 392 C₂₂H₂₄F₃N₃O₃ 436.0 17.1 79 992 393 C₂₁H₂₄BrN₃O₂ 430.0 18.0 84 993 394 C₂₁H₂₄ClN₃O₂ 386.0 16.4 85 994 395 C₂₁H₂₄BrN₃O₂ 430.0 17.2 80 995 396 C₂₁H₂₃F₂N₃O₂ 388.0 15.1 78 996 397 C₂₁H₂₃Cl₂N₃O₂ 420.0 11.7 56 997 398 C₂₂H₂₇N₃O₂ 366.0 13.1 72 998 399 C₂₆H₂₉N₃O₂ 416.0 15.8 76 999 400 C₂₂H₂₆N₄O₄ 411.0 17.4 85 1000 401 C₂₄H₂₉N₃O₄ 424.0 16.9 80 1001 402 C₂₃H₂₆F₃N₃O₂ 434.0 17.7 82 1002 403 C₂₃H₂₅F₄N₃O₂ 452.0 18.6 82 1003 404 C₂₃H₂₆F₃N₃O₃ 450.0 17.8 79 1004 405 C₂₂H₂₆BrN₃O₂ 444.0 17.9 81 1005 406 C₂₂H₂₆ClN₃O₂ 400.0 15.5 78 1006 407 C₂₂H₂₆BrN₃O₂ 444.0 17.8 80 1007 408 C₂₂H₂₅F₂N₃O₂ 402.0 15.6 78 1008 409 C₂₂H₂₅Cl₂N₃O₂ 434.0 17.6 81 1009 410 C₂₅H₃₃N₃O₂ 408.0 16.2 79 1010 411 C₂₉H₃₅N₃O₂ 458.5 18.8 82 1011 412 C₂₅H₃₂N₄O₄ 453.0 19.4 86 1012 413 C₂₇H₃₅N₃O₄ 466.0 19.8 85 1013 414 C₂₆H₃₂F₃N₃O₂ 476.0 20.2 85 1014 415 C₂₆H₃₁F₄N₃O₂ 494.0 20.5 83 1015 416 C₂₆H₃₂F₃N₃O₃ 492.0 19.5 79 1016 417 C₂₅H₃₂BrN₃O₂ 486.0 19.1 79 1017 418 C₂₅H₃₂ClN₃O₂ 442.0 17.7 80 1018 419 C₂₅H₃₂BrN₃O₂ 486.0 20.3 83 1019 420 C₂₅H₃₁F₂N₃O₂ 444.0 18.6 84 1020 421 C₂₅H₃₁Cl₂N₃O₂ 476.0 19.4 81 1021 422 C₂₅H₃₃N₃O₂ 408.0 14.4 71 1022 423 C₂₉H₃₅N₃O₂ 458.0 16.4 72 1023 424 C₂₅H₃₂N₄O₄ 453.0 18.1 80 1024 425 C₂₇H₃₅N₃O₄ 466.0 16.4 70 1025 426 C₂₆H₃₂F₃N₃O₂ 476.0 17.3 73 1026 427 C₂₆H₃₁F₄N₃O₂ 494.0 18.8 76 1027 428 C₂₆H₃₂F₃N₃O₃ 492.0 18.4 75 1028 429 C₂₅H₃₂BrN₃O₂ 486.0 17.9 74 1029 430 C₂₅H₃₂ClN₃O₂ 442.0 15.7 71 1030 431 C₂₅H₃₂BrN₃O₂ 486.0 17.7 73 1031 432 C₂₅H₃₁F₂N₃O₂ 444.0 16.6 75 1032 433 C₂₅H₃₁Cl₂N₃O₂ 476.0 18.7 78 1033 1016 C₂₂H₂₃ClF₃N₃O₂ 454 32.5* 53 1034 1017 C₂₁H₂₄ClN₃O₂ 386 55.2* Q Notes: *indicates “yield (mg) of trifluoroacetate”. Q means “Quantitative”.

Reference Example 16 Synthesis of 3-carbamoyl-1-(4-chlorobenzyl)piperidine

Triethylamine (7.0 mL, 50 mmol) and 4-chlorobenzyl chloride (8.05 g, 50 mmol) were added to a solution of nipecotamide (6.40 g, 50 mmol) in acetonitrile (150 mL) and ethanol (20 mL). The resulting reaction mixture was stirred at 50° C. for 16 hours and cooled to room temperature. A saturated aqueous solution of NaHCO₃ (50 mL) and water (150 mL) were then added, and the resulting mixture was extracted with ethyl acetate (150 mL×3). The extracts were washed with brine, dried over Na₂SO₄ and concentrated to afford a light-red solid. The obtained crude solid was washed with ether (100 mL) to provide 3-carbamoyl-1-(4-chlorobenzyl)piperidine (6.98 g, 54%).

Reference Example 17 Synthesis of 3-(aminomethyl)-1-(4-chlorobenzyl)piperidine

3-Carbamoyl-1-(4-chlorobenzyl)piperidine (3.80 g, 15 mmol) was dissolved in THF (30 mL), and 1 M BH₃-THF (9.4 mL) was added to the obtained solution. The resulting mixture was stirred at 70° C. for 15 hours. After cooling to 0° C., a 2 M hydrochloric acid (50 mL) was added, and the mixture was stirred at room temperature for another 3 hours, basicified with an 4 M aqueous solution of NaOH and extracted with ethyl acetate (100 mL×3). The extracts were combined, washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated. The obtained crude product was purified by column chromatography (SiO₂, ethyl acetate/ethanol/triethylamine=80:15:5) to thereby provide 3-(aminomethyl)-1-(4-chlorobenzyl)piperidine (2.05 g, 55%). ¹H NMR (CDCl₃, 400 MHz) δ 1.00-1.09 (m, 1H), 1.50-1.87 (m, 7H), 1.97-2.06 (m, 1H), 2.65-2.77 (m, 2H), 3.16-3.26 (m, 2H), 3.32 (s, 2H), 3.40 (d, J=13.3 Hz, 1H), 3.49 (d, J=13.3 Hz, 1H), 7.22-7.33 (m, 5H).

Example 1035 Synthesis of 3-[(N-benzoylglycyl)amino]methyl-1-(4-chlorobenzyl)piperidine (Compd. No. 434)

A chloroform (0.4 mL) solution of benzoyl chloride (0.060 mmol) was added to a chloroform (1.0 mL) solution of 3-[(glycylamino)methyl]-1-(4-chlorobenzyl)piperidine (0.050 mmol) and triethylamine (0.070 mmol). The resulting reaction mixture was shaken at room temperature for 2.5 hours, and an (aminomethyl)polystyrene resin (1.04 mmol/g, 50 mg, 50 mmol) was then added to the obtained mixture. The resulting mixture was shaken at room temperature for 12 hours and filtered, and the resin was washed with dichloromethane (0.5 mL). The filtrate and washings were combined, and dichloromethane (4 mL) was added. The obtained mixture was washed with an 2 M aqueous solution of NaOH (0.5 mL) and concentrated to thereby afford 3-[(N-benzoylglycyl)amino]methyl-1-(4-chlorobenzyl)piperidine (Compd. No. 434) -(14.7 mg, 74%). The purity was determined by RPLC/MS (91%). ESI/MS m/e 400 (M⁺+H, C₂₂H₂₆ClN₃O₂).

Examples 1036 to 1058

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1035. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 24.

TABLE 24 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1036 435 C₂₆H₂₈ClN₃O₂ 450 16.0 71 1037 436 C₂₂H₂₅ClN₄O₄ 445 18.9 85 1038 437 C₂₄H₂₈ClN₃O₄ 458 18.2 79 1039 438 C₂₃H₂₅ClF₃N₃O₂ 468 19.0 81 1040 439 C₂₃H₂₄ClF₄N₃O₂ 486 20.2 83 1041 440 C₂₃H₂₅ClF₃N₃O₃ 484 18.9 78 1042 441 C₂₂H₂₅BrClN₃O₂ 478 19.2 80 1043 442 C₂₂H₂₅Cl₂N₃O₂ 434 17.3 80 1044 443 C₂₂H₂₅BrClN₃O₂ 478 18.8 79 1045 444 C₂₂H₂₄ClF₂N₃O₂ 436 16.7 77 1046 445 C₂₂H₂₄Cl₃N₃O₂ 468 17.9 76 1047 446 C₂₃H₂₈ClN₃O₂ 414 14.6 71 1048 447 C₂₇H₃₀ClN₃O₂ 464 17.0 73 1049 448 C₂₃H₂₇ClN₄O₄ 459 19.5 85 1050 449 C₂₅H₃₀ClN₃O₄ 472 17.1 72 1051 450 C₂₄H₂₇ClF₃N₃O₂ 482 19.4 81 1052 451 C₂₄H₂₆ClF₄N₃O₂ 500 18.2 73 1053 452 C₂₄H₂₇ClF₃N₃O₃ 498 18.8 76 1054 453 C₂₃H₂₇BrClN₃O₂ 492 19.4 79 1055 454 C₂₃H₂₇Cl₂N₃O₂ 448 16.5 74 1056 455 C₂₃H₂₇BrClN₃O₂ 492 19.3 78 1057 456 C₂₃H₂₆ClF₂N₃O₂ 450 17.1 76 1058 457 C₂₃H₂₆Cl₃N₃O₂ 482 16.9 70

Reference Example 18 Synthesis of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine

K₂CO₃ (3.02 g) and 4-chlorobenzyl chloride (3.52 g, 21.8 mmol) were successively added to an acetonitrile (100 mL) solution of 4-(aminomethyl)piperidine (7.00 g, 61.3 mmol). The resulting reaction mixture was stirred at 60° C. for 16 hours, cooled to 25° C. and concentrated. The obtained residue was fractionated between dichloromethane (75 mL) and water (50 mL) and then washed with water (50 mL×2) and brine (50 mL×1). The organic layer was dried (over MgSO₄), concentrated and then purified by chromatography (SiO₂, 4% H₂O-^(i)PrOH) to provide 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (3.58 g, 69%).

Example 1059 Synthesis of 4-[(N-benzoylglycyl)amino]methyl-1-(4-chlorobenzyl)piperidine (Compd. No. 458)

Hippuric acid (38 mg, 0.21 mmol), EDCI (48 mg, 0.24 mmol), HOBt (31 mg, 0.23 mmol) and triethylamine (38 μL, 0.27 mmol) were added to a dichloromethane (1 mL) solution of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (50 mg, 0.21 mmol). The resulting reaction mixture was shaken at 25° C. for 16 hours, then diluted with 1 mL of dichloromethane, washed with a 2 M aqueous solution of NaOH (0.75 mL×2), dried (over MgSO₄), concentrated and purified by chromatography (SiO₂, 6-8% methanol/dichloromethane) to thereby afford 4-[(N-benzoylglycyl)amino]methyl-1-(4-chlorobenzyl)piperidine (Compd. No. 458). The resulting compound was treated with TFA to provide a TFA salt (105 mg, 97%). The purity was determined by RPLC/MS (85%). ESI/MS m/e 400 (M⁺+H, C₂₂H₂₆ClN₃O₂).

Examples 1060 to 1086

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1059. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 25.

TABLE 25 Ex- Compd. Yield Yield ample No. Molecular Formula ESI/MS m/e (mg) (%) 1060 459 C₂₃H₂₈ClN₃O₂ 414  86* 78 1061 460 C₂₃H₂₈ClN₃O₂ 414 55 Q 1062 461 C₂₃H₂₅ClF₃N₃O₂ 468 65 Q 1063 462 C₂₃H₂₈ClN₃O₂ 414 61 Q 1064 463 C₂₃H₂₈ClN₃O₂ 414 54 Q 1065 464 C₂₅H₃₂ClN₃O₅ 490 56 Q 1066 465 C₂₁H₂₅ClN₄O₂ 401 38 96 1067 466 C₂₂H₂₅ClN₄O₄ 445 15 34 1068 557 C₂₃H₂₈ClN₃O₂ 414  58* 66 1069 558 C₂₃H₂₈ClN₃O₂ 414 55 Q 1070 618 C₂₅H₃₂ClN₃O₂ 442 58 Q 1071 686 C₂₆H₃₄ClN₃O₂ 456 62 Q 1072 749 C₃₄H₃₇ClN₄O₂ 569    7.2* 18 1073 750 C₂₄H₃₀ClN₃O₃ 444    4.7* 14 1074 840 C₂₄H₂₉ClN₂O₂ 413  52* 58 1075 841 C₂₃H₂₇ClN₂O₂ 399 52 Q 1076 842 C₂₃H₂₆Cl₂N₂O₂ 433 55 Q 1077 843 C₂₅H₃₁ClN₂O₂ 427 58 Q 1078 844 C₂₄H₂₉ClN₂O₂ 413 56 Q 1079 845 C₂₄H₂₉ClN₂O₄S 477 62 Q 1080 846 C₂₉H₃₁ClN₂O₃ 491 43 88 1081 847 C₂₄H₂₈ClFN₂O₃ 447 54 Q 1082 848 C₂₅H₃₁ClN₂O₂ 427 47 Q 1083 849 C₂₅H₃₁ClN₂O₄ 459 55 Q 1084 850 C₂₂H₂₇ClN₂O₃S 435 46 Q 1085 873 C₂₀H₂₈ClN₃O₂ 378   44.8 Q 1086 874 C₂₃H₂₇Cl₂N₃O₃ 464 51 Q Notes: *indicates “yield (mg) of trifluoroacetate”. Q means “Quantitative”.

Reference Example 19 Synthesis of 1-(4-chlorobenzyl)-4-[N-(3,3-diphenylpropyl)aminomethyl]piperidine

4-(Aminomethyl)-1-(4-chlorobenzyl)piperidine (120 mg) was reacted with 3,3-diphenylpropyl methanesulfonate (1.0 equivalent) in the presence of NaI (2.6 equivalents) in acetonitrile at 70° C. for 16 hours. After treatment by a conventional method, the obtained crude product was purified by column chromatography (SiO₂) to afford 1-(4-chlorobenzyl)-4-[N-(3,3-diphenylpropyl)aminomethyl]piperidine (118 mg, 54%). The purity was determined by RPLC/MS (98%).

Reference Example 20 Synthesis of 1-(4-chlorobenzyl)-4-[N-(2,2-diphenylethyl)aminomethyl]piperidine

4-(Aminomethyl)-1-(4-chlorobenzyl)piperidine (120 mg) was subjected to reducing amination in methanol by using 2,2-diphenylacetaldehyde (0.66 equivalent) and a polymer-supported boron hydride at 25° C. for 16 hours and then subjected to treatment according to a conventional method and column chromatography (SiO₂) to thereby provide 1-(4-chlorobenzyl)-4-[N-(2,2-diphenylethyl)aminomethyl]piperidine (70 mg, 49%). The purity was determined by RPLC/MS (98%).

Example 1087 Synthesis of 4-[N-(N-benzoylglycyl)-N-(2,2-diphenylethyl)aminomethyl]-1-(4-chlorobenzyl)piperidine (Compd. No. 524)

Hippuric acid (1.1 equivalents), HBTU (1.1 equivalents) and HOBt (1.1 equivalents) were added to a dichloromethane solution of 1-(4-chlorobenzyl)-4-[N-(2,2-diphenylethyl)aminomethyl]piperidine (0.084 mmol). The resulting reaction mixture was stirred at 40° C. for 24 hours. The obtained crude product was subjected to treatment according to a conventional method and preparative TLC (SiO₂) to thereby provide 4-[N-(N-benzoylglycyl)-N-(2,2-diphenylethyl)aminomethyl]-1-(4-chlorobenzyl)piperidine (Compd. No. 524) (8.5 mg, 17%). The purity was determined by RPLC/MS (98%). ESI/MS m/e 580 (M⁺+H, C₃₆H₃₈ClN₃O₂).

Examples 1088 to 1090

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1087. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 26.

TABLE 26 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1088 521 C₃₈H₃₉ClF₃N₃O₂ 662 5.5 10 1089 522 C₃₇H₃₇ClF₃N₃O₂ 648 8.6 16 1090 523 C₃₇H₄₀ClN₃O₂ 594 4.8 10

Reference Example 21 Synthesis of 1-(4-chlorobenzyl)-4-[(valylamino)methyl]piperidine

Triethylamine (0.76 mL, 5.44 mmol), dl-N-(tert-butoxycarbonyl)valine (1.09 g, 5.03 mmol), EDCI (883 mg, 4.61 mmol) and HOBt (623 mg, 4.61 mmol) were added to a dichloromethane (21 mL) solution of 4-(aminomethyl)-1-(4-chlorobenzyl)piperidine (1.0 g, 4.2 mmol). The resulting reaction mixture was stirred at 25° C. for 16 hours, then diluted with dichloromethane (20 mL), washed with a 2 M aqueous solution of NaOH (20 mL×2) and brine (20 mL×1), dried (over MgSO₄) and concentrated. The obtained crude product was purified by chromatography (SiO₂, 3% methanol/dichloromethane) to thereby afford 1-(4-chlorobenzyl)-4-[[(N-Boc-valyl)amino]methyl]piperidine (1.1 g, 60%) as a light amber oil. ESI/MS m/e 438 (M⁺+H).

1-(4-Chlorobenzyl)-4-[[(N-Boc-valyl)amino]methyl]piperidine (1.1 g, 2.51 mmol) was dissolved in a 3 M HCl-methanol solution (25 mL) and stirred at 25° C. for 1 hour. The resulting reaction mixture was concentrated, and the obtained salt was dissolved in ^(t)BuOH/H₂O=3:1 (25 mL). An anion (OH⁻) exchange resin was added until the solution became slightly basic. The obtained mixture was filtered and concentrated to provide 1-(4-chlorobenzyl)-4-[(valylamino)methyl]piperidine (819 mg, 97%). Further purification was not required for the resulting compound. ESI/MS m/e 338.1 (M⁺+H, C₁₈H₂₈ClN₃O).

Other 4-[(acylamino)methyl]-1-(4-chlorobenzyl)piperidines were synthesized by using the respective corresponding starting materials and reactants according to the method of Reference Example 21.

1-(4-chlorobenzyl)-4-[(glycylamino)methyl]piperidine: 0.830 g, 67% (two steps), ESI/MS 269 (M⁺+H).

1-(4-chlorobenzyl)-4-[(serylamino)methyl]piperidine: 0.286 g, 20% (two steps), ESI/MS 326 (M⁺+H).

4-[(alanylamino)methyl]-1-(4-chlorobenzyl)piperidine: 1.20 g, 65% (two steps), ESI/MS 310 (M⁺+H).

1-(4-chlorobenzyl)-4-[(prolylamino)methyl]piperidine: 1.48 g, 86% (two steps), ESI/MS 336 (M⁺+H).

1-(4-chlorobenzyl)-4-[(glutaminylamino)methyl]piperidine: 0.830 g, 27% (two steps), ESI/MS 367 (M⁺+H).

1-(4-chlorobenzyl)-4-[((2-methylalanyl)amino)methyl]piperidine: 2.24 g, 62% (two steps), ESI/MS 324 (M⁺+H).

1-(4-chlorobenzyl)-4-[((O-methylseryl)amino)methyl]piperidine: 0.686 g, 38% (two steps), ESI/MS 340 (M⁺+H).

1-4-chlorobenzyl)-4-[((1-aminocyclopropylcarbonyl)amino)methyl]piperidine: 2.03 g, 82% (two steps), ESI/MS 322 (M⁺+H).

1-(4-chlorobenzyl)-4-[(leucylamino)methyl]piperidine: 1.30 g, 58% (two steps), ESI/MS 352 (M⁺+H).

1-(4-chlorobenzyl)-4: [((O-benzylseryl)amino)methyl]piperidine: 1.34 g, 56% (two steps), ESI/MS 416 (M⁺+H).

Reference Example 22 Synthesis of 1-(tert-butoxycarbonyl)-4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]piperidine

Triethylamine (3.51 g), N-(9-fluorenylmethyloxycarbonyl)glycine (7.93 g, 26.7 mmol), EDCI (3.80 g) and HOBt (4.33 g) were added to a dichloromethane (150 mL) solution of 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine (5.72 g). The resulting reaction mixture was stirred at room temperature for 18 hours, then washed with water (100 mL×3) and brine (100 mL×2), dried over anhydrous sodium sulfate, concentrated and recrystallized from acetonitrile/methanol (150 mL/1 mL) at 0° C. to provide 1-(tert-butoxycarbonyl)-4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]piperidine (5.75 g, 44%) as an off-white crystal.

Reference Example 23 Synthesis of 4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]piperidine

1-(tert-Butoxycarbonyl)-4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]piperidine (3.17 g, 6.42 mmol) was added to a 4 M dioxane solution of HCl. The resulting solution was stirred at room temperature for 5 hours and concentrated to afford 4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]piperidine (3.85 g) as an off-white solid. The obtained product was used without further purification.

Reference Example 24 Synthesis of 4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]-1-(4-methylthiobenzyl)piperidine

4-Methylthiobenzaldehyde (1.24 g) and NaBH(OAc)₃ (2.56 g) were added to a 1% acetic acid/DMF (15 mL) solution of 4-[[N-(9-fluorenylmethyloxycarbony)glycyl]aminomethyl]piperidine (1.00 g, 2.33 mmol). The resulting reaction mixture was stirred at 60° C. for 1 hour, cooled to room temperature and concentrated. A saturated aqueous solution (50 mL) of NaHCO₃ was added to the resultant residue, and the obtained mixture was extracted with ethyl acetate (50 mL×2). The extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by column chromatography (SiO₂, 50%-10% methanol-dichloromethane) to thereby afford 4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]-1-(4-methylthiobenzyl)piperidine (602 mg) as a colorless oil.

Reference Example 25 Synthesis of 1-(4-ethylbenzyl)-4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]piperidine

4-Ethylbenzaldehyde (1.09 g, 8.16 mmol) and NaBH₃CN (6.59 g, 10.5 mmol) were added to a 2.5% acetic acid/methanol (80 mL) solution of 4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]piperidine (1.00 g, 2.33 mmol). The resulting reaction mixture was stirred at 60° C. for 13 hours and cooled to room temperature. A 1 M aqueous solution of NaOH (50 mL) and dichloromethane (50 mL) were then added, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (50 mL×3). The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by column chromatography (SiO₂, methanol/ethyl acetate=2:8) to thereby provide 1-(4-ethylbenzyl)-4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]piperidine (740 mg, 62%).

Reference Example 26 Synthesis of 4-[(glycylamino)methyl]-1-(4-methylthiobenzyl)piperidine

A DMF (4 mL) solution of 4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]-1-(4-methylthiobenzyl)piperidine (590 mg) and piperidine (1 mL) was stirred at 60° C. for 2 hours. After concentrating, the obtained crude product was purified by column chromatography (SiO₂,triethylamine/methanol/dichloromethane=1:1:9) to thereby afford 4-[(glycylamino)methyl]-1-(4-methylthiobenzyl)piperidine (365 mg) as a white solid. ¹H NMR (CDCl₃, 270 MHz) δ 1.25 (dd, J=12 Hz, 4.1 Hz, 2H), 1.34 (dd, J=12 Hz, 4.1 Hz, 2H), 1.51 (br-s, 2H), 1.66 (d, J=12 Hz, 2H), 1.77 (d, J=7.3 Hz, 1H), 1.94 (t, J=9.5 Hz, 2H), 2.48 (s, 3H), 2.80 (d, J=12 Hz, 2H), 3.18 (t, J=6.2 Hz, 2H), 3.35 (s, 2H), 3.45 (s, 2H), 7.18-7.29 (m, 4H), 7.35 (br-s, 1H).

Further, 1-(4-ethylbenzyl)-4-[(glycylamino)methyl]piperidine was synthesized by using the corresponding starting material and reactants according to the method of Reference Example 26: 333 mg, 79%.

Reference Example 27 Synthesis of 4-[(glycylamino)methyl]-1-(4-fluorobenzyl)piperidine

An acetonitrile (200 mL) solution of 4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]piperidine (1.50 g, 3.49 mmol), 4-fluorobenzyl bromide (0.478 mL, 3.84 mmol) and triethylamine (1.47 mL, 10.5 mmol) was stirred at room temperature for 13 hours. The obtained product was purified by column chromatography (SiO₂, 10% methanol/dichloromethane) to thereby provide 4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]piperidine.

A DMF (5 mL) solution of the 4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]piperidine and piperidine (5 mL) was further stirred at room temperature for 17 hours. After concentrating, the obtained crude product was purified by column chromatography (SiO₂, triethylamine/methanol/dichloromethane=0.5:2:8) to afford 4-[(glycylamino)methyl]-1-(4-fluorobenzyl)piperidine (453 mg, 46%).

Reference Example 28 Synthesis of 4-[(glycylamino)methyl]-1-[4-(N-phenylcarbamoyl)benzyl]piperidine

An acetonitrile (100 mL) solution of 4-(N-phenylcarbamoyl)benzyl chloride (800 mg, 3.26 mmol) was dropped into a mixture of 4-[[N-(9-fluorenylmethyloxycarbonyl)glycyl]aminomethyl]piperidine (1.27 g, 2.96 mmol) with triethylamine (1.25 mL, 8.88 mmol), KI (50 mg, 0.30 mmol) and acetonitrile (200 mL). The resulting mixture was stirred at room temperature for 19 hours and stirred at 60° C. for another 5 hours. After concentrating, the obtained crude product was purified by column chromatography (SiO₂, 5% methanol/dichloromethane-triethylamine/methanol/dichloromethane=2:2:96) to provide 4-[(glycylamino)methyl]-1-[4-(N-phenylcarbamoyl)benzyl]piperidine (340 mg, 30%).

Example 1091 Synthesis of 1-(4-chlorobenzyl)-4-[[N-(3-cyanobenzoyl)valyl]aminomethyl]piperidine (Compd. No. 619)

Triethylamine (0.011 mL, 0.077 mmol), m-cyanobenzoic acid (28 mg, 0.071 mmol), EDCI (13 mg, 0.065 mmol) and HOBt (9 mg, 0.065 mmol) were added to a dichloromethane (0.60 mL) solution of 1-(4-chlorobenzyl)-4-[(valylamino)methyl]piperidine (20 mg, 0.059 mmol). The resulting reaction mixture was stirred at 25° C. for 16 hours, and the obtained solution was diluted with dichloromethane (0.75 mL), washed with a 2 M aqueous solution of NaOH (0.75 mL×2) and dried by filtration through a PTFE membrane. The dried solution was concentrated to thereby afford 1-(4-chlorobenzyl)-4-[[N-(3-cyanobenzoyl)valyl]aminomethyl]piperidine (Compd. No. 619) (24.2 mg, 88%). Further purification was not required for the resulting compound. The purity was determined by RPLC/MS (85%). ESI/MS m/e 467 (M⁺+H, C₂₆H₃₁ClN₄O₂).

Examples 1092 to 1543

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1091. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 27.

TABLE 27 Compd. ESI/MS Yield Yield Example No. Molecular Formula m/e (mg) (%) 1092 467 C₂₂H₂₅BrClN₃O₂ 478 11 46 1093 468 C₂₄H₃₁ClN₄O₂ 443  9 41 1094 469 C₂₃H₂₈ClN₃O₃ 430  7* 27 1095 470 C₂₃H₂₅ClN₄O₂ 425 21 Q 1096 471 C₂₄H₂₈ClN₃O₄ 458  7 29 1097 472 C₂₉H₃₁N₃O₃ 504  5* 21 1098 473 C₂₄H₂₈ClN₃O₃ 442 16 71 1099 474 C₂₃H₂₅ClF₃N₃O₂ 468 14 60 1100 475 C₂₅H₃₂ClN₃O₂ 442  5 22 1101 476 C₂₂H₂₅ClN₄O₄ 445  4 17 1102 477 C₂₅H₃₂ClN₃O₃ 458  10* 36 1103 478 C₂₁H₂₇ClN₄O₂ 403  9 47 1104 479 C₂₀H₂₄ClN₃O₃ 390 17 87 1105 480 C₂₀H₂₃BrClN₃O₃ 470 23 Q 1106 481 C₂₀H₂₄ClN₃O₂S 406  7 33 1107 482 C₂₁H₂₆ClN₃O₂S 420  9 45 1108 483 C₂₁H₂₆ClN₃O₂S 420  8 40 1109 484 C₂₄H₂₇ClN₄O₂ 439  9* 34 1110 485 C₂₄H₂₄ClF₆N₃O₂ 536 13 49 1111 486 C₂₃H₂₅ClN₄O₂ 425 16 74 1112 487 C₂₂H₂₅Cl₂N₃O₂ 434  5 24 1113 488 C₂₂H₂₇ClN₄O₂ 415  7 32 1114 489 C₂₄H₂₄ClF₆N₃O₂ 536 21 78 1115 490 C₂₄H₃₀ClN₃O₃ 444  8 35 1116 491 C₂₃H₂₄ClF₄N₃O₂ 486 19 79 1117 492 C₂₃H₂₅ClF₃N₃O₃ 484 18 76 1118 493 C₂₃H₂₄Cl₂F₃N₃O₂ 502 23 92 1119 494 C₂₃H₂₄ClF₄N₃O₂ 486 19 79 1120 495 C₂₃H₂₄ClF₄N₃O₂ 486 20 83 1121 496 C₂₃H₂₄ClF₄N₃O₂ 486 12 48 1122 497 C₂₅H₃₂ClN₃O₃ 458  4 16 1123 498 C₂₃H₂₆ClF₃N₄O₂ 483 13 52 1124 499 C₂₄H₃₁ClN₄O₂ 443  8 36 1125 500 C₂₃H₂₈ClN₃O₃ 430 10 48 1126 501 C₂₂H₂₄BrClN₄O₄ 523 10 39 1127 502 C₂₂H₂₄ClFN₄O₄ 463  4 17 1128 503 C₂₂H₂₄Cl₂N₄O₄ 479 12 52 1129 504 C₂₄H₃₀ClN₃O₄ 460 11 43 1130 505 C₂₂H₂₄BrClN₄O₄ 523  2  8 1131 506 C₂₀H₂₃ClN₄O₅ 435  2 10 1132 507 C₂₁H₂₆ClN₃O₃ 404  9 44 1133 508 C₂₄H₂₆ClN₃O₂S 456  1  5 1134 509 C₂₀H₂₃BrClN₃O₂S 484 12 48 1135 510 C₂₂H₂₈ClN₃O₃ 418  9 44 1136 511 C₂₄H₃₂ClN₃O₃ 446  9 40 1137 512 C₂₅H₂₉ClN₄O₂ 453 10 45 1138 513 C₂₄H₂₈ClN₃O₃ 442  9 41 1139 514 C₂₆H₃₄ClN₃O₂ 456 11 49 1140 515 C₂₃H₂₈ClN₃O₃ 430  5 24 1141 525 C₂₃H₂₈ClN₃O₄S 478 20 85 1142 526 C₂₀H₂₄ClN₃O₃ 390  6 31 1143 527 C₂₀H₂₄ClN₃O₂S 406  8 39 1144 528 C₂₅H₃₀ClF₃N₄O₄ 543   28.2 95 1145 529 C₂₀H₂₃ClN₄O₄S 451  9 39 1146 530 C₃₁H₃₃ClN₄O₂ 529  5 17 1147 531 C₂₁H₂₆ClN₃O₃S 436  8 37 1148 532 C₂₂H₂₈ClN₃O₃ 418  8 40 1149 533 C₂₁H₂₆ClN₃O₃ 404  6 32 1150 534 C₂₁H₂₅ClN₄O₅ 449  5 20 1151 535 C₂₂H₂₆ClN₃O₃S 448  8 37 1152 536 C₂₃H₃₁ClN₄O₂ 431  6 28 1153 537 C₂₅H₃₄ClN₃O₃ 460  8 34 1154 538 C₂₇H₃₀ClN₃O₃ 480  9 36 1155 539 C₂₂H₂₅ClF₃N₃O₃ 472 18 75 1156 540 C₂₅H₂₉ClN₄O₂ 453  8 36 1157 541 C₂₂H₂₆ClN₅O₄ 460   2.4 10 1158 542 C₂₄H₃₀ClN₃O₂ 428    4.6* 51 1159 543 C₂₄H₃₀ClN₃O₂ 428   20.6* 71 1160 544 C₂₂H₂₅ClFN₃O₂ 418   15.8* 56 1161 545 C₂₂H₂₄Cl₃N₃O₂ 468    7.3* 23 1162 546 C₂₂H₂₄Cl₃N₃O₂ 468   17.4* 55 1163 547 C₂₂H₂₄Cl₃N₃O₂ 468   14.1* 44 1164 548 C₂₂H₂₄Cl₃N₃O₂ 468    6.8* 22 1165 549 C₂₂H₂₄Cl₂N₄O₄ 479    5.7* 18 1166 550 C₂₂H₂₄Cl₂N₄O₄ 479   18.9* 58 1167 551 C₂₄H₃₀ClN₃O₂ 428   14.2* 49 1168 552 C₂₄H₂₇ClF₃N₃O₂ 482   30.6* 94 1169 553 C₂₅H₂₆ClF₆N₃O₂ 550   38.0* Q 1170 554 C₂₄H₂₆ClFN₄O₂ 457    0.9*  3 1171 555 C₂₄H₂₆Cl₂N₄O₂ 473   11.1* 35 1172 556 C₂₅H₂₉ClN₄O₂ 453   12.5* 41 1173 559 C₂₅H₂₆ClF₆N₃O₂ 550 15 72 1174 560 C₂₄H₂₇ClN₄O₂ 439 12 68 1175 561 C₂₃H₂₇BrClN₃O₂ 494 14 73 1176 562 C₂₃H₂₇Cl₂N₃O₂ 448 13 75 1177 563 C₂₅H₂₆ClF₆N₃O₂ 550 14 66 1178 564 C₂₅H₃₂ClN₃O₃ 458  5 28 1179 565 C₂₄H₂₆ClF₄N₃O₂ 500 12 61 1180 566 C₂₄H₂₇ClF₃N₃O₃ 498 12 62 1181 567 C₂₄H₂₆Cl₂F₃N₃O₂ 516 12 61 1182 568 C₂₄H₂₆ClF₄N₃O₂ 500 15 77 1183 569 C₂₄H₂₆ClF₄N₃O₂ 500 11 59 1184 570 C₂₄H₂₆ClF₄N₃O₂ 500 16 84 1185 571 C₂₆H₃₄ClN₃O₃ 472 14 77 1186 572 C₂₄H₂₈ClF₃N₄O₂ 497 11 55 1187 573 C₂₁H₂₅BrClN₃O₂S 500 12 64 1188 574 C₂₁H₂₅BrClN₃O₂S 500 15 75 1189 575 C₂₅H₃₄ClN₃O₃ 460 16 87 1190 576 C₂₂H₂₈ClN₃O₂S₂ 466 13 71 1191 577 C₂₂H₂₈ClN₃O₃ 418 12 72 1192 578 C₂₅H₂₈ClN₃O₂S 470 15 81 1193 579 C₂₅H₂₉ClN₄O₂ 453 17 94 1194 580 C₂₂H₂₈ClN₃O₂S 434 15 91 1195 581 C₂₁H₂₆ClN₃O₂S 420 13 80 1196 582 C₂₂H₂₈ClN₃O₂S 434 10 59 1197 583 C₂₆H₃₁ClN₄O₂ 467  6 31 1198 584 C₃₀H₃₂ClN₃O₃ 518 18 92 1199 585 C₂₄H₂₇ClN₄O₂ 439 14 85 1200 586 C₂₃H₂₇Cl₂N₃O₂ 448 17 97 1201 587 C₂₄H₂₇ClF₃N₃O₂ 482 17 91 1202 588 C₂₃H₂₉ClN₄O₂ 429  5 29 1203 589 C₂₇H₃₆ClN₃O₂ 470  4 24 1204 590 C₂₆H₃₄ClN₃O₂ 456  6 36 1205 591 C₂₅H₃₃ClN₄O₂ 457  7 38 1206 592 C₂₄H₃₀ClN₃O₃ 444  4 20 1207 593 C₂₄H₃₀ClN₃O₃ 444  2 14 1208 594 C₂₃H₂₈ClN₃O₃ 430  4 25 1209 595 C₂₅H₃₀ClN₃O₄ 472  7 38 1210 596 C₂₅H₃₀ClN₃O₃ 456  7 40 1211 597 C₂₅H₃₀ClN₃O₃ 456 15 85 1212 598 C₂₁H₂₆ClN₃O₃ 404 15 94 1213 599 C₂₂H₂₉ClN₄O₂ 417  5 30 1214 600 C₂₁H₂₅BrClN₃O₃ 484  6 34 1215 601 C₂₄H₃₀ClN₃O₃ 444  5 28 1216 602 C₂₅H₃₃ClN₄O₂ 457  5 28 1217 603 C₂₃H₂₉ClN₄O₂ 429  4 22 1218 604 C₂₁H₂₇ClN₄O₂ 403  9 58 1219 605 C₂₁H₂₆ClN₃O₃ 404 17 87 1220 606 C₂₁H₂₆ClN₃O₂S 420 15 74 1221 607 C₂₂H₂₈ClN₃O₃S 450 31 Q 1222 608 C₂₃H₃₀ClN₃O₃ 432 17 80 1223 609 C₂₂H₂₈ClN₃O₃ 418 18 89 1224 610 C₂₃H₂₈ClN₃O₃S 462 20 86 1225 611 C₂₆H₃₆ClN₃O₃ 474 21 90 1226 612 C₂₈H₃₂ClN₃O₃ 494 20 84 1227 613 C₂₃H₂₇ClF₃N₃O₃ 486 19 81 1228 614 C₂₄H₃₃ClN₄O₂ 445 23 Q 1229 615 C₂₅H₂₉ClN₄O₂ 453  4 20 1230 616 C₃₂H₃₅ClN₄O₂ 543 11 40 1231 617 C₂₅H₂₇ClF₃N₃O₂ 482   6.7 37 1232 620 C₂₅H₃₁BrClN₃O₂ 520 15 49 1233 621 C₂₅H₃₁Cl₂N₃O₂ 476 18 64 1234 622 C₂₇H₃₇ClN₄O₂ 485 14 50 1235 623 C₂₆H₃₄ClN₃O₃ 472 19 69 1236 624 C₂₅H₃₁ClN₄O₄ 487 21 73 1237 625 C₂₅H₃₃ClN₄O₂ 457 19 69 1238 626 C₂₇H₃₀ClF₆N₃O₂ 578  8 25 1239 627 C₂₇H₃₆ClN₃O₃ 486 16 55 1240 628 C₂₇H₃₄ClN₃O₄ 500 24 80 1241 629 C₂₆H₃₀ClF₄N₃O₂ 528 18 56 1242 630 C₂₆H₃₁ClF₃N₃O₃ 526 21 68 1243 631 C₂₆H₃₀Cl₂F₃N₃O₂ 544 15 48 1244 632 C₂₆H₃₀ClF₄N₃O₂ 528 13 41 1245 633 C₂₆H₃₀ClF₄N₃O₂ 528 20 63 1246 634 C₂₆H₃₀ClF₄N₃O₂ 528 19 62 1247 635 C₂₈H₃₈ClN₃O₃ 500 11 36 1248 636 C₂₆H₃₄ClN₃O₂ 456 21 89 1249 637 C₂₆H₃₁ClF₃N₃O₂ 510 20 95 1250 638 C₂₆H₃₁ClN₄O₂ 467 15 54 1251 639 C₂₇H₃₇ClN₄O₂ 485 19 66 1252 640 C₂₆H₃₄ClN₃O₃ 472 16 56 1253 641 C₂₇H₃₄ClN₃O₄ 500 18 59 1254 642 C₃₂H₃₆ClN₃O₃ 546 24 73 1255 643 C₂₆H₃₁ClF₃N₃O₂ 510 16 54 1256 644 C₂₉H₄₀ClN₃O₂ 498 18 61 1257 645 C₂₅H₃₃ClN₄O₂ 457 22 78 1258 646 C₂₆H₃₄ClN₃O₃ 472 13 47 1259 647 C₂₇H₃₄ClN₃O₃ 500 13 46 1260 648 C₂₈H₃₈ClN₃O₂ 484 17 60 1261 649 C₂₈H₃₈ClN₃O₃ 500   12.5 42 1262 650 C₃₂H₃₆ClN₃O₃ 546  1*  2 1263 651 C₂₈H₃₅ClN₄O₂ 495  4* 12 1264 652 C₂₅H₃₁ClN₄O₄ 487  5* 14 1265 653 C₃₀H₄₂ClN₃O₃ 528  1*  3 1266 654 C₂₇H₃₄ClN₃O₃ 484  7* 21 1267 655 C₂₆H₃₂ClF₃N₄O₂ 525  6* 16 1268 656 C₂₃H₃₀ClN₃O₃ 432  6* 18 1269 657 C₂₃H₃₀ClN₃O₂S 448  4* 13 1270 658 C₂₇H₃₃ClN₄O₂  48  1*  4 1271 659 C₂₃H₂₉ClN₄O₄S 493  4* 10 1272 660 C₃₄H₃₉ClN₄O₂ 571  3*  7 1273 661 C₂₄H₃₂ClN₃O₃S 478  3*  7 1274 662 C₂₅H₃₄ClN₃O₃ 460  2*  6 1275 663 C₂₄H₃₂ClN₃O₃ 446  2*  5 1276 664 C₂₄H₃₁ClN₄O₅ 491  2*  5 1277 665 C₂₅H₃₂ClN₃O₃S 490  1*  3 1278 666 C₂₆H₃₇ClN₄O₂ 473  3*  7 1279 667 C₃₀H₃₆ClN₃O₃ 522  3*  7 1280 668 C₂₅H₃₁ClF₃N₃O₃ 514  2*  6 1281 669 C₂₄H₃₃ClN₄O₂ 445  15* 45 1282 670 C₂₃H₂₉BrClN₃O₃ 510  3*  7 1283 671 C₂₃H₂₉ClN₄O₅ 477  2*  5 1284 672 C₂₃H₃₁ClN₄O₂ 431  2*  7 1285 673 C₂₃H₃₀ClN₃O₂S 448  2*  6 1286 674 C₂₄H₃₂ClN₃O₂S 462  3*  9 1287 675 C₂₄H₃₂ClN₃O₂S 462  1*  4 1288 676 C₂₇H₃₃ClN₄O₂ 482  2*  6 1289 677 C₂₈H₃₅ClN₄O₂ 495  2*  6 1290 678 C₂₄H₃₂ClN₃O₃ 446  3*  9 1291 679 C₂₇H₃₂ClN₃O₂S 498  1*  3 1292 680 C₂₃H₂₉BrClN₃O₂S 526  2*  6 1293 681 C₂₅H₃₄ClN₃O₃ 460  2*  5 1294 682 C₂₇H₃₈ClN₃O₃ 488  2*  4 1295 683 C₂₄H₃₂ClN₃O₂S₂ 494  1*  4 1296 684 C₂₆H₃₆ClN₃O₄S₂ 554  2*  5 1297 685 C₂₄H₃₂ClN₃O₄S₂ 526  3*  7 1298 687 C₂₅H₃₀ClN₃O₂ 440 24 Q 1299 688 C₂₇H₂₈ClF₆N₃O₂ 576 28 98 1300 689 C₂₆H₂₉ClN₄O₂ 465 23 99 1301 690 C₂₅H₂₉BrClN₃O₂ 518 26 99 1302 691 C₂₇H₃₅ClN₄O₂ 483 24 97 1303 692 C₂₆H₃₂ClN₃O₃ 470 24 Q 1304 693 C₂₇H₂₈ClF₆N₃O₂ 576 16 55 1305 694 C₂₇H₃₄ClN₃O₃ 484 25 Q 1306 695 C₂₇H₃₂ClN₃O₄ 498 12 47 1307 696 C₂₆H₂₉ClF₃N₃O₃ 524 25 95 1308 697 C₂₆H₂₉ClN₄O₂ 465 15 64 1309 698 C₂₇H₃₅ClN₄O₂ 483 24 Q 1310 699 C₂₆H₃₂ClN₃O₃ 470 26 Q 1311 700 C₂₇H₃₂ClN₃O₄ 498 15 62 1312 701 C₂₇H₃₂ClN₃O₃ 482 11 44 1313 702 C₂₆H₂₉ClF₃N₃O₂ 508 23 94 1314 703 C₂₈H₃₆ClN₃O₂ 482 26 Q 1315 704 C₂₅H₂₉ClN₄O₄ 485 11 43 1316 705 C₂₄H₃₀ClN₃O₂S 460 25 Q 1317 706 C₂₄H₃₀ClN₃O₂S 460 25 Q 1318 707 C₂₆H₂₉ClF₃N₃O₂ 508 15 55 1319 708 C₂₃H₂₇BrClN₃O₂S 526 25 92 1320 709 C₂₄H₃₀ClN₃O₂S₂ 492 26 Q 1321 710 C₂₃H₂₇BrClN₃O₂S 526 25 94 1322 711 C₂₅H₃₂ClN₃O₃ 458 26 Q 1323 712 C₂₇H₃₀ClN₃O₂S 496 26 Q 1324 713 C₂₄H₃₀ClN₃O₃ 444 26 Q 1325 714 C₂₈H₃₃ClN₄O₂ 493 12 50 1326 715 C₂₃H₂₈ClN₃O₂S 446 24 Q 1327 716 C₂₇H₃₁ClN₄O₂ 479 32 Q 1328 717 C₂₃H₂₁ClN₄O₅ 475 23 95 1329 718 C₂₃H₂₉ClN₄O₂ 429 24 Q 1330 719 C₂₃H₂₈ClN₃O₃ 430 24 Q 1331 720 C₂₃H₂₇BrClN₃O₃ 510 24 95 1332 721 C₂₄H₃₁ClN₄O₂ 443 22 98 1333 722 C₂₆H₃₂ClN₃O₃ 470  9 37 1334 723 C₂₅H₃₁ClN₄O₂ 455 10 44 1335 724 C₂₉H₃₈ClN₃O₂ 496 28 Q 1336 725 C₃₂H₃₄ClN₃O₃ 544 26 95 1337 726 C₂₇H₃₃ClN₄O₃ 497  3 11 1338 727 C₂₅H₂₉Cl₂N₃O₂ 474 25 Q 1339 728 C₂₅H₃₁ClN₄O₂ 455 21 92 1340 729 C₂₅H₂₉ClN₄O₄ 485 26 Q 1341 730 C₂₅H₂₉Cl₂N₃O₂ 474 21 90 1342 731 C₂₇H₃₂ClN₃O₃ 482 10 41 1343 732 C₂₆H₂₈ClF₄N₃O₂ 526 27 Q 1344 733 C₂₈H₃₆ClN₃O₃ 498 22 89 1345 734 C₂₆H₂₈ClF₄N₃O₂ 526 25 94 1346 735 C₂₆H₂₈ClF₄N₃O₂ 526 23 87 1347 736 C₂₆H₃₀ClF₃N₄O₂ 523 24 78 1348 737 C₂₆H₂₈ClF₄N₃O₂ 526 21 66 1349 738 C₂₅H₃₂ClN₃O₃ 458 23 84 1350 739 C₂₇H₃₁ClN₄O₂ 479 19 66 1351 740 C₂₄H₃₁ClN₄O₅ 489 23 77 1352 741 C₂₃H₂₇ClN₄O₄S 491 26 88 1353 742 C₂₄H₃₀ClN₃O₃S 476 23 82 1354 743 C₂₃H₂₈ClN₃O₃ 430 21 81 1355 744 C₂₆H₃₂ClN₃O₂ 454 25 91 1356 745 C₂₇H₃₆ClN₃O₃ 486 23 80 1357 746 C₂₆H₃₅ClN₄O₂ 471 27 96 1358 747 C₂₅H₂₉ClF₃N₃O₃ 512 23 74 1359 748 C₂₃H₂₈ClN₃O₂S 446 22 82 1360 751 C₂₄H₃₀ClN₃O₃ 444  3 11 1361 752 C₂₅H₂₆ClF₆N₃O₃ 566  7 20 1362 753 C₂₄H₂₇ClN₄O₃ 455  6 22 1363 754 C₂₃H₂₇Cl₂N₃O₃ 464  8 29 1364 755 C₂₄H₃₀ClN₃O₄ 460  6 22 1365 756 C₂₃H₂₇ClN₄O₅ 475  5 18 1366 757 C₂₅H₃₂ClN₃O₄ 474  5 18 1367 758 C₂₅H₃₀ClN₃O₅ 488  5 18 1368 759 C₂₄H₂₇ClF₃N₃O₄ 514  6 20 1369 760 C₂₄H₂₆ClF₄N₃O₃ 516  6 18 1370 761 C₂₄H₂₆ClF₄N₃O₃ 516  3 10 1371 762 C₂₄H₂₇ClF₃N₃O₃ 498  2 95 1372 763 C₂₃H₂₈ClN₃O₃ 430  4 95 1373 764 C₂₄H₃₀ClN₃O₂ 428  9 42 1374 765 C₂₅H₃₂ClN₃O₂ 442 10 47 1375 766 C₂₅H₂₉ClF₃N₃O₂ 496 10 42 1376 767 C₂₅H₃₂ClN₃O₄S 506  8 32 1377 768 C₂₄H₂₉BrClN₃O₂ 506  9 35 1378 769 C₂₅H₂₉ClF₃N₃O₃ 512  6 22 1379 770 C₂₅H₂₈ClF₄N₃O₂ 514  3 10 1380 771 C₂₅H₂₈ClF₄N₃O₂ 514 10 37 1381 772 C₂₅H₂₉ClF₃N₃O₂ 496  8 33 1382 773 C₂₆H₃₆ClN₃O₃ 474 10 41 1383 774 C₂₃H₃₀ClN₃O₂S₂ 480 12 50 1384 775 C₂₇H₃₈ClN₃O₃ 488 14 57 1385 776 C₂₉H₃₄ClN₃O₃ 508 12 49 1386 777 C₂₄H₂₉ClF₃N₃O₃ 500 22 87 1387 778 C₂₄H₂₈Cl₂N₄O₄ 507  6 22 1388 779 C₂₄H₂₉Cl₂N₃O₂ 462 10 46 1389 780 C₂₄H₂₉ClN₄O₄ 473 15 65 1390 781 C₂₆H₃₁ClN₄O₂ 467  7* 20 1391 782 C₂₅H₃₂ClN₃O₃ 458  8* 23 1392 783 C₂₆H₃₄ClN₃O₃ 472  7* 19 1393 784 C₂₆H₃₁ClF₃N₃O₂ 510  7* 17 1394 785 C₂₆H₃₄ClN₃O₄ 488  6* 17 1395 786 C₂₄H₂₈ClN₃O₂ 426 22  9 1396 787 C₂₅H₃₀ClN₃O₂ 440 21 94 1397 788 C₂₅H₂₇ClF₃N₃O₂ 494  4* 14 1398 789 C₂₅H₃₀ClN₃O₄S 504  9 35 1399 790 C₂₄H₂₇Cl₂N₃O₂ 460  5* 16 1400 791 C₂₄H₂₇ClN₄O₄ 471  3* 10 1401 792 C₂₅H₂₇ClF₃N₃O₃ 510  5* 16 1402 793 C₂₅H₂₆ClF₄N₃O₂ 511  5* 16 1403 794 C₂₅H₂₆ClF₄N₃O₂ 512  5* 16 1404 795 C₂₅H₂₇ClF₃N₃O₂ 494  6* 21 1405 796 C₂₃H₂₈ClN₃O₂S₂ 478  4* 14 1406 797 C₂₇H₃₆ClN₃O₃ 486  7* 29 1407 798 C₂₉H₃₂ClN₃O₃ 506  3 13 1408 799 C₂₄H₂₇ClF₃N₃O₃ 498  3* 11 1409 800 C₂₄H₂₆Cl₂N₄O₄ 505  5* 15 1410 801 C₂₆H₂₉ClN₄O₂ 465 12 41 1411 802 C₂₅H₃₀ClN₃O₃ 456  5* 15 1412 803 C₂₆H₃₂ClN₃O₃ 470  6* 16 1413 804 C₂₆H₂₉ClF₃N₃O₂ 508  8* 20 1414 805 C₂₆H₃₂ClN₃O₄ 486  6* 15 1415 806 C₂₄H₂₇BrClN₃O₂ 506  5* 14 1416 807 C₂₇H₃₂ClN₅O₃ 510   29.7 Q 1417 808 C₂₆H₃₃ClN₄O₃ 485   29.9 Q 1418 809 C₂₅H₃₀Cl₂N₄O₃ 505   30.2 Q 1419 810 C₃₀H₃₅ClN₄O₄ 551   31.0 Q 1420 811 C₂₅H₂₉Cl₂N₅O₅ 550   30.4 Q 1421 812 C₂₄H₃₁ClN₄O₃S₂ 523   25.0 88 1422 813 C₂₆H₃₀ClF₃N₄O₃ 539   20.5 70 1423 814 C₂₆H₃₀ClF₃N₄O₄ 555   22.7 75 1424 815 C₂₆H₂₉ClF₄N₄O₃ 557   25.8 85 1425 816 C₂₆H₃₀ClF₃N₄O₃ 539   25.3 86 1426 817 C₂₆H₂₉ClF₄N₄O₃ 557   26.8 88 1427 818 C₂₅H₃₀BrClN₄O₃ 551   27.1 90 1428 819 C₂₇H₂₉ClF₆N₄O₃ 607   13.9 42 1429 820 C₂₅H₃₀ClN₅O₅ 516   14.1 51 1430 821 C₂₄H₂₈Cl₂N₄O₅ 523 40 86 1431 822 C₂₃H₃₀ClN₃O₃S₂ 496 41 93 1432 823 C₂₆H₃₁ClN₄O₃ 483 43 Q 1433 824 C₂₇H₃₈ClN₃O₄ 503 37 83 1434 825 C₂₉H₃₄ClN₃O₄ 524 28 61 1435 826 C₂₄H₂₉ClF₃N₃O₄ 516 40 87 1436 827 C₂₆H₃₁ClN₄O₃ 483 31 72 1437 828 C₂₅H₂₉ClF₃N₃O₄ 528 40 86 1438 829 C₂₅H₂₈ClF₄N₃O₃ 530 45 97 1439 830 C₂₅H₂₈ClF₄N₃O₃ 530 35 74 1440 831 C₂₄H₂₉BrClN₃O₃ 523 45 98 1441 832 C₂₄H₂₉Cl₂N₃O₃ 478 38 91 1442 833 C₂₄H₂₉ClN₄O₅ 488 38 87 1443 834 C₂₅H₂₉ClF₃N₃O₃ 512 42 93 1444 835 C₂₄H₃₀ClN₃O₃ 444 43 Q 1445 836 C₂₅H₃₂ClN₃O₃ 458 37 91 1446 837 C₂₅H₂₉ClF₃N₃O₃ 512 41 91 1447 838 C₂₆H₃₄ClN₃O₄ 488 34 78 1448 839 C₂₇H₃₆ClN₃O₆ 534 37 71 1449 942 C₂₇H₃₀ClF₆N₃O₂ 578 17 48 1450 997 C₂₆H₃₄ClN₃O₂ 456    7.6* 23 1451 998 C₂₇H₃₃ClF₃N₃O₂ 524  6 15 1452 999 C₂₇H₃₆ClN₃O₂ 470  8 24 1453 1000 C₂₇H₃₆ClN₃O₃ 486  9 24 1454 1001 C₂₈H₃₈ClN₃O₃ 500  4 10 1455 1002 C₂₇H₃₃ClF₃N₃O₃ 540  9 23 1456 1003 C₂₈H₃₈ClN₃O₂ 484  7 21 1457 1004 C₂₈H₃₈ClN₃O₄ 516 11 30 1458 1005 C₂₉H₄₀ClN₃O₅ 547  9 23 1459 1006 C₃₀H₄₂ClN₃O₄ 544  8 21 1460 1007 C₃₂H₄₆ClN₃O₅ 589  7 17 1461 1008 C₂₅H₃₁ClN₄O₃ 471 25 79 1462 1009 C₂₆H₃₃ClN₄O₄ 501 35 97 1463 1010 C₂₇H₃₅ClN₄O₄ 515 35  9 1464 1011 C₂₇H₃₅ClN₄O₃ 499 32 54 1465 1012 C₂₇H₃₅ClN₄O₅ 531 27 77 1466 1013 C₂₈H₃₇ClN₄O₆ 561 14 37 1467 1014 C₂₉H₃₉ClN₄O₅ 559 24 66 1468 1015 C₃₁H₄₃ClN₄O₆ 603 25 65 1469 1018 C₂₆H₃₄ClN₃O₄ 488   13.0* 39 1470 1019 C₂₈H₃₈ClN₃O₅ 532   13.4* 37 1471 1020 C₂₅H₃₂ClN₃O₄ 474   12.7* 40 1472 1021 C₂₆H₂₈ClF₆N₃O₄ 596   13.8* 34 1473 1022 C₂₅H₃₂ClN₃O₄ 474   14.2* 37 1474 1023 C₂₅H₃₂ClN₃O₂ 442   11.5* 32 1475 1024 C₂₆H₃₄ClN₃O₅ 504   12.0* 30 1476 1025 C₂₇H₃₆ClN₃O₄ 502   14.7* 37 1477 1026 C₂₉H₄₀ClN₃O₅ 546   13.5* 32 1478 1027 C₂₆H₃₄ClN₃O₄ 488   11.9* 31 1479 1028 C₂₇H₃₀ClF₆N₃O₄ 610   14.6* 31 1480 1029 C₂₅H₃₂ClN₃O₃ 458   14.0* 38 1481 1030 C₂₄H₂₇ClF₃N₃O₃ 498   14.0* 35 1482 1031 C₂₄H₃₀ClN₃O₃ 444   10.4* 29 1483 1032 C₂₅H₃₂ClN₃O₄ 474   14.9* 39 1484 1033 C₂₅H₃₂ClN₃O₂ 442   13.3* 37 1485 1034 C₂₆H₃₄ClN₃O₅ 504   13.7* 34 1486 1035 C₂₇H₃₆ClN₃O₄ 502   16.7* 42 1487 1036 C₂₉H₄₀ClN₃O₅ 547   15.5* 36 1488 1037 C₂₆H₃₄ClN₃O₄ 488   14.1* 36 1489 1038 C₂₇H₃₀ClF₆N₃O₄ 610   17.5* 37 1490 1039 C₂₅H₃₂ClN₃O₃ 458   15.1* 41 1491 1040 C₂₄H₂₇ClF₃N₃O₃ 498   15.4* 39 1492 1041 C₂₄H₃₀ClN₃O₃ 444   12.7* 35 1493 1042 C₂₂H₂₆BrClN₄O₂ 495   10.4* 25 1494 1043 C₂₂H₂₆Cl₂N₄O₂ 449   11.1* 29 1495 1044 C₂₃H₂₉ClN₄O₂ 429    5.2* 14 1496 1045 C₂₃H₂₉ClN₄O₃ 445   12.4* 33 1497 1046 C₂₂H₂₅Cl₃N₄O₂ 483   10.0* 25 1498 1047 C₂₄H₃₁ClN₄O₂ 443   12.1* 32 1499 1048 C₂₅H₃₃ClN₄O₅ 505   16.1* 39 1500 1049 C₂₃H₂₈BrClN₄O₂ 507   12.0* 29 1501 1050 C₂₈H₃₈ClN₃O₄ 516   39.2* Q 1502 1051 C₂₈H₃₈ClN₃O₂ 484   34.0* Q 1503 1052 C₂₉H₄₀ClN₃O₅ 546   14.5* 39 1504 1053 C₃₀H₄₂ClN₃O₄ 544   11.8* 32 1505 1054 C₃₂H₄₆ClN₃O₅ 588   12.2* 31 1506 1055 C₂₉H₄₀ClN₃O₄ 530   44.5* Q 1507 1056 C₃₀H₃₆ClF₆N₃O₄ 652   46.0* Q 1508 1057 C₂₈H₃₈ClN₃O₃ 500   11.2* Q 1509 1058 C₂₇H₃₆ClN₃O₃ 486   35.5* Q 1510 1059 C₂₇H₃₃ClF₃N₃O₃ 540   41.4* Q 1511 1060 C₂₉H₄₀ClN₃O₄ 530   13.6* 37 1512 1061 C₃₀H₃₆ClF₆N₃O₄ 652   44.2* Q 1513 1062 C₂₈H₃₈ClN₃O₃ 500   39.9* Q 1514 1063 C₂₇H₃₆ClN₃O₃ 486   12.0* 35 1515 1064 C₂₇H₃₃ClF₃N₃O₃ 540   37.8* Q 1516 1065 C₂₈H₃₈ClN₃O₄ 516   12.3* 34 1517 1066 C₂₈H₃₈ClN₃O₂ 484   30.7* 90 1518 1067 C₂₉H₄₀ClN₃O₅ 546   13.8* 37 1519 1068 C₃₀H₄₂ClN₃O₄ 544   13.1* 35 1520 1069 C₃₂H₄₆ClN₃O₅ 589   14.1* 35 1521 1070 C₂₉H₃₄ClN₃O₃S₂ 572   38.3 93 1522 1071 C₃₂H₃₅ClN₄O₃ 559   39.6 98 1523 1072 C₃₃H₄₂ClN₃O₄ 580   40.9 98 1524 1073 C₃₅H₃₈ClN₃O₄ 600   40.5 94 1525 1074 C₃₀H₃₃ClF₃N₃O₄ 592   38.7 91 1526 1075 C₃₁H₃₃ClF₃N₃O₄ 604 38 87 1527 1076 C₃₀H₃₃ClN₄O₅ 565   38.5 94 1528 1077 C₃₁H₃₃ClF₃N₃O₃ 588   35.8 84 1529 1078 C₃₀H₃₄ClN₃O₃ 520   34.7 93 1530 1079 C₃₁H₃₆ClN₃O₃ 534   38.4 Q 1531 1080 C₃₂H₃₈ClN₃O₄ 564   39.3 97 1532 1081 C₃₃H₄₀ClN₃O₆ 610   45.5 Q 1533 1082 C₂₈H₃₆ClN₃O₃ 498    4.1* 10 1534 1083 C₂₈H₃₆ClN₃O₃ 498    6.4* 16 1535 1125 C₃₀H₃₂Cl₂N₄O₅ 599    3.4*  8 1536 1126 C₃₀H₃₂BrClN₄O₅ 644    3.4*  7 1537 1127 C₃₂H₃₅ClN₄O₃ 559    1.6*  4 1538 1128 C₃₁H₃₂ClF₄N₃O₃ 606    4.3* 10 1539 1129 C₃₁H₃₂ClF₄N₃O₃ 606    5.9* 14 1540 1130 C₃₀H₃₃BrClN₃O₃ 599    5.7* 13 1541 1131 C₃₀H₃₃Cl₂N₃O₃ 554    6.4* 16 1542 1132 C₃₁H₃₃ClF₃N₃O₃ 588    6.3* 15 1543 1167 C₂₇H₃₄ClN₃O₃ 484    1.8*  4 Notes: *indicates “yield (mg) of trifluoroacetate”. Q means “Quantitative”.

Example 1544 Synthesis of 1-(4-chlorobenzyl)-4-[[N-(3,5-bis(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 1213)

A dichloromethane (1 mL) solution of 3,5-bis(trifluoromethyl)benzoyl chloride (0.058 mmol) was added to a mixture of 1-(4-chlorobenzyl)-4-[(glycylamino)methyl]piperidine (0.050 mmol) with chloroform (0.2 mL), a piperidinomethylpolystyrene (58 mg) and dichloromethane (0.75 mL). The resulting reaction mixture was stirred at room temperature for 2 hours, and methanol (1.0 mL) was then added to the obtained mixture. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was loaded onto a Varian™ SCX column and washed with methanol (16 mL). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (6 mL) and concentrated to thereby provide 1-(4-chlorobenzyl)-4-[[N-(3,5-bis(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 1213) (24.0 mg, 90%). The purity was determined by RPLC/MS (100%). ESI/MS m/e 536.2 (M⁺+H, C₂₄H₂₄ClF₆N₃O₂).

Examples 1545 to 1547

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1544. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 28.

TABLE 28 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1545 1214 C₂₃H₂₄ClF₄N₃O₃ 486.2 22.2 91 1546 1215 C₂₂H₂₄Cl₃N₃O₂ 467.9 20.9 89 1547 1216 C₂₂H₂₄ClF₂N₃O₂ 436.0 19.3 89

Example 1548 Synthesis of 4-[[N-(3-bromo-4-methylbenzoyl)glycyl]aminomethyl]-1-(4-chlorobenzyl)piperidine (Compd. No. 1113)

3-Bromo-4-methylbenzoic acid (0.060 mmol), diisopropylcarbodiimide (0.060 mmol) and HOBt (0.060 mmol) were added to a solution of 1-(4-chlorobenzyl)-4-[(glycylamino)methyl]piperidine (0.050 mmol) in chloroform (1.35 mL) and tert-butanol (0.15 mL). The resulting reaction mixture was stirred at room temperature for 15 hours. The mixture was then loaded onto a Varian™ SCX column and washed with methanol/chloroform=1:1 (12 mL) and methanol (12 mL). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated to thereby afford 4-[[N-(3-bromo-4-methylbenzoyl)glycyl]aminomethyl]-1-(4-chlorobenzyl)piperidine (Compd. No. 1113) (16.1 mg, 65%). The purity was determined by RPLC/MS (95%). ESI/MS m/e 494.0 (C₂₃H₂₇BrClN₃O₂).

Examples 1549 to 1619

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of 1548. The obtained products, if necessary, were purified by preparative TLC to provide the objective compounds. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 29.

Compd. No. 1422 was obtained as a by-product of Compd. No. 1418: 5.6 mg, yield: 25%; ESI/MS m/e 447.2 (C₂₂H₂₇ClN₄O₂S).

TABLE 29 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1549 1114 C₂₂H₂₄BrClFN₃O₂ 498.0 20.2 81 1550 1115 C₂₂H₂₄Cl₂FN₃O₂ 452.2 18.6 82 1551 1116 C₂₃H₂₇ClIN₃O₂ 539.1 21.9 81 1552 1117 C₂₃H₂₇ClN₄O₄ 459.2 18.7 81 1553 1187 C₂₃H₂₇BrClN₃O₂ 494.0 22.1 90 1554 1188 C₂₄H₂₇ClN₄O₃ 455.2 17.2 76 1555 1189 C₂₅H₂₉ClN₄O₃ 469.2 21.1 90 1556 1190 C₂₂H₂₆ClFN₄O₂ 433.2 20.4 94 1557 1241 C₂₃H₂₄Cl₂F₃N₃O₂ 502.0 22.5 90 1558 1242 C₂₃H₂₇ClFN₃O₂ 432.2 21.2 98 1559 1243 C₂₃H₂₇Cl₂N₃O₂ 448.0 21.6 96 1560 1244 C₂₂H₂₆ClIN₄O₂ 541.0 26.4 98 1561 1245 C₂₂H₂₅ClF₂N₄O₂ 451.0 21.3 94 1562 1246 C₂₁H₂₇ClN₄O₂ 403.2 19.4 96 1563 1247 C₂₈H₃₀ClN₃O₂S 524.0 24.7 94 1564 1248 C₂₂H₂₅ClN₄O₅ 461.0 20.7 90 1565 1282 C₂₅H₂₆ClF₃N₄O₃ 523.2 25.0 96 1566 1283 C₂₃H₂₇Cl₂N₃O₃ 464.2 12.2 53 1567 1284 C₂₂H₂₅BrClN₃O₃ 496.0 24.1 97 1568 1285 C₂₂H₂₅Cl₂N₃O₃ 450.2 21.8 97 1569 1342 C₂₂H₂₄BrCl₂N₃O₂ 514.0 27.2 Q 1570 1343 C₂₃H₂₇Cl₂N₃O₂ 448.0 21.4 95 1571 1344 C₂₂H₂₄Cl₂IN₃O₂ 560.0 27.0 96 1572 1345 C₂₃H₂₈ClN₃O₂ 430.2 23.8 Q 1573 1346 C₂₂H₂₅ClIN₃O₃ 542.0 29.4 Q 1574 1350 C₂₁H₂₆ClN₃O₂S 420.0 13.0 62 1575 1354 C₂₄H₂₈BrClN₄O₃ 537.2 5.2 19 1576 1358 C₂₃H₂₆ClN₅O₂ 440.2 21.8 99 1577 1383 C₂₃H₂₄Cl₂F₃N₃O₂ 502.0 20.0 80 1578 1384 C₂₀H₂₃BrClN₃O₂S 486.0 21.0 87 1579 1385 C₂₈H₃₀ClN₃O₄S 540.2 23.8 88 1580 1386 C₂₈H₃₀ClN₃O₂ 476.0 20.0 84 1581 1414 C₂₄H₂₈Cl₂N₄O₃ 491.0 0.8  3 1582 1418 C₂₃H₂₆ClN₅O₂S 472.0 10.4 44 1583 1436 C₂₉H₃₀ClN₃O₃ 504.2 26.8 Q 1584 1600 C₂₃H₂₆ClF₃N₄O₂ 483.2 16.5 68 1585 1601 C₂₃H₂₆ClF₃N₄O₃ 499.0 20.0 80 1586 1602 C₂₁H₂₄BrClN₄O₂ 481.0 18.1 75 1587 1603 C₂₁H₂₄Cl₂N₄O₂ 435.0 5.5 25 1588 1604 C₂₇H₃₀ClN₃O₃ 492.0 18.6 76 1589 1605 C₂₁H₂₇ClN₄O₂ 415.2 18.1 87 1590 1609 C₂₃H₂₅N₃O₂S 500.0 18.3 73 1591 1659 C₂₂H₂₆Cl₂N₄O₂ 449.0 366.0 83 1592 1664 C₂₄H₂₉F₃N₄O₂S 495.2 13.7 55 1593 1665 C₂₄H₂₉F₃N₄O₃S 511.2 14.9 58 1594 1666 C₂₃H₂₈F₂N₄O₂S 463.2 12.9 56 1595 1667 C₂₂H₂₇Br₂N₃O₃ 542 26.1 96 1596 1668 C₂₄H₃₀F₂N₄O₂ 445 22.9 Q 1597 1669 C₂₄H₃₁FN₄O₂ 427 24.0 Q 1598 1670 C₂₄H₃₁IN₄O₂ 535 28.1 Q 1599 1671 C₂₅H₃₁F₃N₄O₃ 493 26.8 Q 1600 1672 C₂₅H₃₁F₃N₄O₂ 478 24.7 Q 1601 1673 C₂₄H₂₉BrClN₃O₂ 508 24.9 98 1602 1674 C₂₀H₂₂Br₂FN₃O₃ 532 25.6 96 1603 1675 C₂₂H₂₅F₃N₄O₂ 435 21.5 99 1604 1676 C₂₂H₂₆F₂N₄O₂ 417 21.4 Q 1605 1677 C₂₂H₂₆BrFN₄O₂ 479 23.4 98 1606 1678 C₂₂H₂₆FIN₄O₂ 525 27.4 Q 1607 1679 C₂₂H₂₆ClFN₄O₂ 433 22.4 Q 1608 1680 C₂₃H₂₆F₄N₄O₃ 483 25.5 Q 1609 1681 C₂₃H₂₆F₄N₄O₂ 467 23.2 99 1610 1682 C₂₃H₂₆BrClFN₃O 498 24.2 98 1611 1683 C₂₇H₂₈Br₂N₄O₄ 633 31.8 Q 1612 1684 C₂₉H₃₁F₂N₅O₃ 536 28.3 Q 1613 1685 C₂₉H₃₂FN₅O₃ 518 31.1 Q 1614 1686 C₂₉H₃₂BrN₅O₃ 578 29.6 Q 1615 1687 C₂₉H₃₂IN₅O₃ 626 32.4 Q 1616 1688 C₂₉H₃₂ClN₅O₃ 534 28.2 Q 1617 1689 C₃₀H₃₂F₃N₅O₄ 584 31.7 Q 1618 1690 C₃₀H₃₂F₃N₅O₃ 568 30.6 Q 1619 1691 C₂₉H₃₀BrClN₄O₃ 599 31.4 Q Note: Q means “Quantitative”.

For example Compd. Nos. 1245 and 1600 exhibited the following NMR spectra.

Comps. No. 1245: ¹H NMR (270 MHz, CDCl₃) δ 1.20-1.97 (m, 7H), 2.80-2.86 (m, 2H), 3.19 (t, J=6.5 Hz, 2H), 3.43 (s, 2H), 4.02 (d, J=5.3 Hz, 2H), 5.52 (br s, 2H), 6.44 (d, J=11.9, 6.6 Hz, 1H), 7.02 (br s, 1H), 7.21-7.32 (m, 5H).

Compd. No. 1600: ¹H NMR (270 MHz, CDCl₃) δ 1.25-1.97 (m, 9H), 2.82-2.87 (m, 2H), 3.21 (t, J=6.5 Hz, 2H), 3.44 (s, 2H), 4.06 (d, J=5.1 Hz, 2H), 5.98 (br s, 1H), 6.71 (d, J=8.3 Hz, 1H), 6.87 (br s, 1H), 7.26 (s, 4H), 7.43 (dd, J=5.9 Hz, 1H), 7.64 (s, 1H).

Example 1620 Synthesis of 1-(4-chorobenzyl)-4-[[N-(4-isopropylphenylsulfonyl)glycyl]aminomethyl]piperidine (Compd. No. 869)

A (piperidinomethyl)polystyrene resin (28 mg, 2.8 mmol/g) and 4-isopropylbenzenesulfonyl chloride (1.5 equivalents) were added to a chloroform (2 mL) solution of 1-(4-chlorobenzyl)-4-[(glycylamino)methyl]piperidine (14.8 mg, 0.05 mmol). The resulting mixture was stirred at 25° C. for 16 hours, then filtered and concentrated to thereby afford 1-(4-chlorobenzyl)-4-[[N-(4-isopropylphenylsulfonyl)glycyl]aminomethyl]piperidine (Compd. No. 869) (22.1 mg, 92%). The purity was determined by RPLC/MS (86%). ESI/MS m/e 478 (M⁺+H, C₂₄H₃₂N₃O₃S).

Examples 1621 to 1627

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1620. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 30.

TABLE 30 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1621 865 C₂₂H₂₈ClN₃O₃S 450 16.2 72 1622 866 C₂₂H₂₅ClF₃N₃O₃S 504 8.8 35 1623 867 C₂₃H₂₄ClF₆N₃O₃S 572 8.0 28 1624 868 C₂₃H₃₀ClN₃O₃S 464 9.6 41 1625 870 C₂₂H₂₈ClN₃O₃S 450 8.8 39 1626 871 C₂₅H₃₄ClN₃O₃S 492 11.1 45 1627 872 C₂₁H₂₆ClN₃O₃S 436 9.6 44

Example 1628 Synthesis of 1-(4-chlorobenzyl-4-[[2-(3-(4-trifluoromethylphenyl)ureido)acetylamino]methyl]piperidine (Compd. No. 852)

A (piperidinomethyl)polystyrene resin (28 mg, 2.8 mmol/g) and 3-(trifluoromethyl)phenyl isocyanate (1.3 equivalents) were added to a chloroform (2 mL) solution of 1-(4-chlorobenzyl)-4-[(glycylamino)methyl]piperidine (14.8 mg, 0.05 mmol). The resulting mixture was stirred at 25° C. for 16 hours, and an (aminomethyl)polystyrene resin was added to the obtained mixture. The resulting mixture was stirred at 25° C. for 16 hours to trap the remaining isocyanate. The obtained mixture was filtered and concentrated to thereby provide 1-(4-chlorobenzyl)-4-[[2-(3-(4-trifluoromethylphenyl)ureido) acetylamino]methyl]piperidine (Comp d. No. 852) (19 mg, 78%). The purity was determined by RPLC/MS (92%). ESI/MS m/e 483 (M⁺+H, C₂₃H₂₆ClF₃N₄O₂).

Examples 1629 to 1641

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1628. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 31.

TABLE 31 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1629 851 C₂₃H₂₆ClF₃N₄O₂ 483 13.2 55 1630 853 C₂₂H₂₇ClN₄O₂ 416 8.5* 32 1631 854 C₂₃H₂₉ClN₄O₂ 429 11.4* 42 1632 855 C₂₃H₂₉ClN₄O₂ 429 10.1* 37 1633 856 C₂₄H₂₉ClN₄O₃ 457 10.3* 36 1634 857 C₂₃H₂₉ClN₄O₃ 445 10.9* 39 1635 858 C₂₃H₂₉ClN₄O₃ 445 8.6* 31 1636 859 C₂₂H₂₆Cl₂N₄O₂ 449 11.0* 39 1637 860 C₂₃H₂₆ClN₅O₂ 440 9.2* 33 1638 861 C₂₂H₂₇ClN₄OS 431 13.3 62 1639 862 C₂₃H₂₉ClN₄OS 445 15.3 69 1640 863 C₂₃H₂₉ClN₄O₂S 461 14.7 64 1641 864 C₂₃H₂₉ClN₄O₂S 461 13.1 57 Note: *indicates “yield (mg) of trifluoroacetate”.

Example 1642 Synthesis of 1-(4-chlorobenzyl)-4-[[N-(3-ethoxybenzoyl)-D-phenylalanyl]aminomethyl]piperidine (Compd. No. 2091)

Triethylamine (0.090 mL), N-(tert-butoxycarbonyl)-D- (phenylalanine) (122 mg), EDCI (89 mg) and HOBt (62 mg) were added to a chloroform (3 mL) solution of 1-(4-chlorobenzyl)-4-(aminomethyl)piperidine (100 mg). The resulting mixture was stirred at room temperature for 17 hours, and the reaction mixture was washed with a 1 M aqueous solution of NaOH (2 mL×2) and brine (2 mL). The organic layer was dried and concentrated to thereby afford 1-(4-chlorobenzyl)-4-[[N-(tert-butoxycarbonyl)-D-phenylalanyl]aminomethyl]piperidine.

The resulting 1-(4-chlorobenzyl)-4-[[N-(tert-butoxycarbonyl)-D-phenylalanyl]aminomethyl]piperidine was dissolved in methanol (5 mL), and a 4 M dioxane solution of HCl was then added to the solution. The obtained solution was stirred at room temperature for 19 hours and concentrated.

Triethylamine (0.090 mL), EDCI (90 mg) and HOBt (68 mg) were added to a chloroform solution (1 mL) of the obtained residue and 3-ethoxybenzoic acid (80 mg, 0.48 mmol). The resulting mixture was stirred at room temperature for 17 hours. The resulting reaction mixture was washed with a 1 M aqueous solution of NaOH (1.5 mLX 2) and brine (1.5 mL). The organic layer was dried, concentrated and purified by column chromatography (SiO₂, dichloromethane/methanol=95:5) to provide 1-(4-chlorobenzyl)-4-[[N-(3-ethoxybenzoyl)-D-phenylalanyl]aminomethyl]piperidine (Compd. No. 2091) (183.5 mg, 82%). The purity was determined by RPLC/MS (99%). ESI/MS m/e 534.0 (M⁺+H, C₃₁H₃₆ClN₃O₃).

Examples 1643 to 1657

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of 1642. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 32.

TABLE 32 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1643 2092 C₃₃H₃₇ClN₄O₃ 572.8 152.9 64 1644 2093 C₂₇H₃₆ClN₃O₃S 518.0 177.4 82 1645 2094 C₂₉H₃₄ClN₃O₃S 539.9 164.4 73 1646 2095 C₂₈H₃₈ClN₃O₃ 500.0 139.1 66 1647 2096 C₃₁H₄₂ClN₃O₃ 540.0 161.7 71 1648 2097 C₂₇H₃₆ClN₃O₃ 485.8 157.8 78 1649 2098 C₃₁H₃₅Cl₂N₃O₃ 567.9 172.2 72 1650 2099 C₃₀H₃₄ClN₃O₃ 519.8 144.7 66 1651 2100 C₃₂H₃₈ClN₃O₄ 564.0 181.5 77 1652 2101 C₃₈H₄₂ClN₃O₄ 639.9 192.3 72 1653 2103 C₃₃H₄₀ClN₃O₄ 577.8 159.9 66 1654 2104 C₂₈H₃₆ClN₃O₅ 530.1 99.7 45 1655 2115 C₂₇H₃₆ClN₃O₃ 486.2 122.9 60 1656 2116 C₂₈H₃₈ClN₃O₃ 500.1 118.3 57 1657 2117 C₂₈H₃₄ClN₅O₃ 524.1 98.3 45

Reference Example 29 Synthesis of 1-(tert-butoxycarbonyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine

N-[3-(Trifluoromethyl)benzoyl]glycine (4.22 g, 17.0 mmol), EDCI (4.25 g, 22.1 mmol), 1-hydroxybenzotriazole hydrate (2.99 g, 22.1 mmol) and triethylamine (1.72 g) were added to an anhydrous dichloromethane (200 mL) solution of 1-(tert-butoxycarbonyl)-4-(aminomethyl)piperidine (4.03 g). The resulting reaction mixture was stirred at 25° C. for 20 hours, and H₂O (100 mL) was then added to the mixture. The obtained mixture was extracted with dichloromethane (50 mLX 2). The extracts were combined, washed with H₂O (50 mL×2) and brine (50 mL), dried (over MgSO₄) and concentrated to thereby afford a yellow oil. The obtained crude product was purified by column chromatography (SiO₂,70% ethyl acetate-hexane) to provide 1-(tert-butoxycarbonyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine as a white solid (6.39 g, 85%). ¹H NMR (CDCl₃, 300 MHz) δ 1.4 (s, 9H), 1.0-1.8 (m, 5H), 2.6-2.8 (m, 2H), 3.15-3.3 (m, 2H), 4.0-4.3 (m, 4H), 6.6-6.7 (m, 1H), 7.64 (s, 1H), 7.60 (dd, 1H, J=7.2, 7.2 Hz), 7.79 (d, 1H, J=7.2 Hz), 8.0 (d, 1H, J=7.2 Hz), 8.11 (s, 1H). The purity was determined by RPLC/MS (97%). ESI/MS m/e 444.3 (M⁺+H, C₂₁H₂₈N₃O₄).

Reference Example 30 Synthesis of 4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine

A 1 M HCl-Et₂O (55 mL) was added to a methanol (40 mL) solution of 1-(tert- butoxycarbonyl)-4-[[N-(3-trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (2.29 g, 5.16 mmol). The obtained mixture was stirred at 25 t for 15 hours, and the solvent was removed under reduced pressure. A 2 M aqueous solution of NaOH (100 mL) was added to the mixture, and the resulting mixture was extracted with ethyl acetate (100 mL×3). The extracts were combined, washed with brine (50 mL), dried (over K₂CO₃) and concentrated to thereby afford a white solid. The obtained crude solid was purified by column chromatography (SiO₂, methanol/dichloromethane/triethylamine=7:6:1) to provide 4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine as a white solid (1.27 g, 72%). The purity was determined by RPLC/MS (98%). ESI/MS m/e 344.1 (M⁺+H, C₁₆H₂₀N₃O₂).

Example 1658 Synthesis of 1-[3-(trifluoromethoxy)benzyl]-4-[(N-(3-(trifluoromethyl)benzoyl)glycyl)aminomethyl]piperidine (Compd. No. 927)

An acetonitrile (1.0 mL) solution of 4-[[N-(3-trifluoromethyl)benzoyl]glycyl]aminomethyl]piperidine (19.9 mg, 0.058 mmol) and a (piperidinomethyl)polystyrene (55 mg, 2.7 mmol base/g resin) were added to an acetonitrile (1.0 mL) solution of 3-(trifluoromethoxy)benzyl bromide (12.3 mg, 0.048 mmol). The obtained mixture was stirred at 60° C. for 2.5 hours. Phenyl isocyanate (6.9 mg, 0.048 mmol) was added to the cooled reaction mixture, and the resulting mixture was stirred at 25° C. for 1 hour. The reaction mixture was loaded onto a Varian™ SCX column and washed with methanol (20 mL). The product was eluted with a 2 M methanol solution of NH₃ and concentrated to provide 1-[3-(trifluoromethoxy)benzyl]-4-[(N-(3-(trifluoromethyl)benzoyl)glycyl)aminomethyl]piperidine (Compd. No. 927) as an off-white oil (22.8 mg, 91%). The purity was determined by RPLC/MS (99%). ESI/MS m/e 518.1 (M⁺+H, C₂₄H₂₅F₆N₃O₃).

Examples 1659 to 1710

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1658. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 33.

TABLE 33 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1659 875 C₂₃H₂₆F₃N₃O₂ 434 6.3 40 1660 876 C₂₃H₂₅BrF₃N₃O₂ 512 4.3 23 1661 877 C₂₄H₂₅F₃N₄O₂ 459 11.3 68 1662 878 C₂₃H₂₅F₃N₄O₄ 479 8.3 48 1663 884 C₂₅H₂₉F₃N₄O₃ 491 10.8 61 1664 885 C₂₄H₂₈F₃N₃O₄S 512 9.0 49 1665 886 C₂₃H₂₅F₄N₃O₂ 452 12.7 78 1666 887 C₂₄H₂₅F₆N₃O₂ 502 13.9 77 1667 888 C₂₃H₂₆F₃N₃O₃ 450 11.5 71 1668 889 C₂₉H₃₀F₃N₃O₂ 510 12.4 68 1669 890 C₂₇H₂₈F₃N₃O₂ 484 12.0 69 1670 891 C₂₃H₂₄Cl₂F₃N₃O₂ 502 11.4 63 1671 892 C₂₄H₂₈F₃N₃O₃ 464 11.7 70 1672 893 C₂₄H₂₆F₃N₅O₅ 522 13.9 74 1673 894 C₂₆H₃₂F₃N₃O₃ 492 11.3 64 1674 895 C₂₄H₂₈F₃N₃O₂ 448 4.8 30 1675 896 C₂₄H₂₅F₃N₄O₂ 459 17.5 Q 1676 897 C₂₄H₂₆F₃N₃O₄ 478 9.2 57 1677 898 C₂₄H₂₆F₃N₃O₄ 478 8.9 55 1678 899 C₂₄H₂₈F₃N₃O₃ 464 13.7 82 1679 900 C₂₅H₂₈F₃N₃O₄ 492 18.6 Q 1680 901 C₂₉H₃₀F₃N₃O₂ 510 13.7 75 1681 902 C₂₃H₂₄F₃N₅O₆ 524 12.6 67 1682 903 C₂₅H₃₀F₃N₃O₄ 494 14.0 79 1683 906 C₂₅H₃₀F₃N₃O₂ 462 11.2 67 1684 907 C₃₁H₃₄F₃N₃O₂ 538 19.6 75 1685 908 C₃₀H₃₁F₃N₄O₃ 553 30.4 76 1686 909 C₃₀H₃₁F₃N₄O₃ 553 12.6 63 1687 910 C₂₃H₂₄Cl₂F₃N₃O₂ 502 11.0 61 1688 911 C₂₃H₂₅ClF₃N₃O₂ 468 20.2 89 1689 912 C₂₃H₂₄Br₂F₃N₃O₂ 590 20.2 95 1690 913 C₂₄H₂₈F₃N₃O₃ 464 12.6 76 1691 914 C₃₀H₃₂F₃N₃O₃ 540 13.9 72 1692 915 C₂₄H₂₈F₃N₃O₃ 464 8.3 25 1693 916 C₂₂H₂₅F₃N₄O₂ 435 2.5  8 1694 917 C₂₂H₂₅F₃N₄O₂ 435 2.7  9 1695 918 C₂₆H₃₀F₃N₃O₄ 506 3.9 22 1696 919 C₂₄H₂₈F₃N₃O₂ 448 15.9 99 1697 920 C₂₄H₂₅F₆N₃O₃ 518 20.3 81 1698 921 C₂₇H₂₈F₃N₃O₂ 484 15.5 89 1699 922 C₂₀H₂₆F₃N₃O₂ 398 7.3 51 1700 923 C₂₉H₂₉ClF₃N₃O₂ 544 12.5 48 1701 928 C₂₄H₂₅F₆N₃O₃ 518 21.4 86 1702 929 C₂₄H₂₈F₃N₃O₂S 480 23.7 Q 1703 930 C₂₄H₂₈F₃N₃O₂ 448 21.3 99 1704 931 C₂₄H₂₅F₃N₄O₂ 459 21.4 97 1705 932 C₂₃H₂₄ClF₃N₄O₄ 513 15.6 63 1706 933 C₂₄H₂₈F₃N₃O₂ 448 16.6 77 1707 934 C₂₂H₂₅F₃N₄O₂ 435 18.0 43 1708 935 C₂₃H₂₅F₃N₄O₄ 479 15.1 65 1709 936 C₂₃H₂₅F₃N₄O₄ 479 15.4 67 1710 1615 C₂₄H₂₅F₆N₃O₂S 534.2 26.3 99 Note: Q means “Quantitative”.

Example 1711 Synthesis of 1-[4-(dimethylamino)benzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 937)

A methanol (1.0 mL) solution of 4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (20.0 mg, 0.058 mmol) and NaBH₃CN (16.5 mg) were added to a 5% acetic acid solution (1.0 mL) of 4-(dimethylamino)benzaldehyde (30.4 mg, 0.204 mmol), and the resulting mixture was stirred at 60° C. for 19 hours. The solvent was evaporated to provide a solid. Acetonitrile (2.0 mL) and phenyl isocyanate (6.9 mg, 0.048 mmol) were added to the solid, and resulting mixture was stirred at 25° C. for 1 hour. The reaction mixture was loaded onto a Varian™ SCX column and washed with methanol (20 mL). The obtained crude product was eluted with a 2 M NH₃-methanol (6 mL), and the eluate was concentrated to thereby afford 1-[4-(dimethylamino)benzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 937) as an off-white oil (13.5 mg, 49%). The purity was determined by RPLC/MS (87%). ESI/MS m/e 477.3 (M⁺+H, C₂₅H₃₁F₃N₄O₂).

Examples 1712 to 1729

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to Example 1711. The obtained products, if necessary, were purified by preparative TLC (SiO₂) to provide the objective compounds. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 34.

TABLE 34 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1712 879 C₂₄H₂₆F₃N₃O₄ 478 13.0 62 1713 880 C₂₄H₂₆F₃N₃O₄ 478 16.3 78 1714 881 C₂₃H₂₅BrF₃N₃O₂ 512 11.4 51 1715 882 C₂₉H₃₀F₃N₃O₃ 526 13.4 58 1716 883 C₂₃H₂₅ClF₃N₃O₂ 468 7.9 39 1717 904 C₂₃H₂₆F₃N₃O₃ 450 3.3 17 1718 905 C₂₁H₂₃F₃N₄O₄S 485 27.7 98 1719 938 C₂₃H₂₄ClF₄N₃O₂ 486 8.6 30 1720 939 C₂₃H₂₄ClF₃N₄O₄ 513 11.0 37 1721 940 C₂₃H₂₆F₃N₃O₃ 450 5.5 21 1722 941 C₂₄H₂₄ClF₆N₃O₂ 536 11.2 36 1723 987 C₃₀H₃₂F₃N₃O₂ 524 17.5 76 1724 1449 C₂₅H₃₀F₃N₃O₂ 462 21.6 80 1725 1450 C₂₆H₃₂F₃N₃O₂ 476 23.5 85 1726 1452 C₂₇H₃₅F₃N₄O₂ 505 5.1 17 1727 1453 C₂₆H₃₂F₃N₃O₃ 492 22.0 77 1728 1454 C₂₅H₃₀F₃N₃O₃ 478 21.4 77 1729 1456 C₂₅H₂₈F₃N₃O₄ 492 23.8 83

Example 1730 Synthesis of 1-[3-hydroxy-4-methoxybenzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 1452)

A 5% acetic acid/methanol (1.0 mL) solution of 4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (20.0 mg, 0.058 mm ol) and 3-hydroxy-4-methoxybenzaldehyde (33 mg) was added to a 5% acetic acid/methanol (1.0 mL) solution of NaBH₃CN (16.5 mg), and the mixture was stirred at 60° C. for 15 hours. The resulting reaction mixture wa's then loaded onto a Varian™ SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a 2 M NH₃-methanol (5 mL) and concentrated to thereby afford 1-[3-hydroxy-4-methoxybenzyl]4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Comp d. No. 1452) (25.8 mg, 92%). The purity was determined by RPLC/MS (91%). ESI/MS m/e 480 (M⁺+H, C₂₄H₂₈F₃N₃O₄).

Examples 1731 to 1733

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1730. The obtained products, if necessary, were purified by preparative TLC to provide the objective compounds. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 35.

TABLE 35 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1731 1455 C₂₄H₂₈F₃N₃O₄ 480 24.0 86 1732 1647 C₂₇H₃₄F₃N₃O₂ 490.2 23.6 96 1733 1649 C₂₆H₃₂F₃N₃O₂ 476.2 23.1 97

Example 1734 Synthesis of 1-(4-benzylbenzyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 926)

A chloroform (1.0 mL) solution of methanesulfonyl chloride (4.2 mg, 0.037 mmol) and a (piperidinomethyl)polystyrene (54 mg, 2.7 mmol base/g resin) were added to a chloroform (1.0 mL) solution of 4-(benzyl)benzyl alcohol (8.7 mg, 0.044 mmol), and the resulting mixture was stirred at 25° C. for 15 hours. 4-[[N-(3-(Trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (15.1 mg, 0.044 mmol) and KI (2 mg) were then added to the reaction mixture, and the resulting mixture solution was further stirred at 65° C. for 5 hours. Phenyl isocyanate (5.2 mg) was added to the cooled reaction mixture, and the obtained mixture was stirred at 25° C. for 1 hour. The resulting reaction mixture was loaded onto a Varian™ SCX column and washed with methanol (20 mL). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated to thereby afford 1-(4-benzylbenzyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 926) as an off-white oil (5.6 mg, 29%). The purity was determined by RPLC/MS (94%). ESI/MS m/e 524.1 (M⁺+H, C₃₀H₃₂F₃N₃O₂).

Reference Example 31 Synthesis of 4-[[(N-(benzyloxycarbonyl)glycyl)amino]methyl]-1-(tert-butoxycarbonyl)piperidine

Triethylamine (2.8 mL, 20 mmol), N-(benzyloxycarbonyl)glycine (3.77 g, 18 mmol), EDCI (3.45 g, 18 mmol) and HOBt (2.43 g, 18 mmol) were added to a chloroform (80 mL) solution of 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine (3.54 g, 16.5 mmol). The resulting mixture was stirred at room temperature for 15 hours, and a 2 M aqueous solution of NaOH (100 mL) was then added to the mixture. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (100 mLX 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by column chromatography (SiO₂, ethyl acetate) to provide 4-[[(N-(benzyloxycarbonyl) glycyl)amino]methyl]-1-(tert-butoxycarbonyl)piperidine as an amorphous solid (6.27 g, 94%).

Reference Example 32 Synthesis of 4-[(glycylamino)methyl]-1-(tert-butoxycarbonyl)piperidine

A methanol (100 mL) solution of 4-[[(N-(benzyloxycarbonyl)glycyl)amino]methyl]-1-(tert-butoxycarbonyl)piperidine (6.26 g, 15.4 mmol) was hydrogenated in the presence of a 5% palladium carbon (620 mg) at room temperature for 7 hours. The catalyst was removed by filtration through Celite, and the filtrate was then concentrated to thereby afford 4-[(glycylamino)methyl]-1-(tert- butoxycarbonyl)piperidine as a solid (3.84 g, 92%).

Reference Example 33 Synthesis of 4-[[(N-(2-amino-5-chlorobenzoyl)glycyl)amino]methyl]-1-(tert-butoxycarbonyl)piperidine

Triethylamine (0.75 mL, 5.4 mmol), 2-amino-5-chlorobenzoic acid (840 mg, 4.9 mmol), EDCI (940 mg, 4.9 mmol) and HOBt (660 mg, 4.9 mmol) were added to a chloroform (25 mL) solution of 4-[(glycylamino)methyl]-1-(tert-butoxycarbonyl)piperidine (1.33 g, 4.90 mmol). The resulting mixture was stirred at room temperature for 3 hours, and a 2 M aqueous solution of NaOH (20 mL) was then added to the mixture. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by column chromatography (SiO₂, ethyl acetate) to thereby provide 4-[[(N-(2-amino-5-chlorobenzoyl) glycyl)amino]methyl]-1-(tert-butoxycarbonyl)piperidine as a solid (1.63 g, 78%).

Reference Example 34 Synthesis of 4-[[(N-(2-amino-5-chlorobenzoyl)glycyl)amino]methyl]piperidine

A 4 M dioxane solution of HCl (9.5 mL) was added to a methanol (20 mL) solution of 4-[[(N-(2-amino-5-chlorobenzoyl)glycyl)amino]methyl]-1-(tert-butoxycarbonyl)piperidine (1.63 g, 3.84 mmol), and the resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated, and a 2 M aqueous solution of NaOH (20 mL) was added to the resulting residue. The obtained mixture was extracted with dichloromethane (20 mLX 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to thereby afford 4-[[(N-(2-amino-5-chlorobenzoyl)glycyl)amino]methyl]piperidine (1.19 g, 95%). ¹H NMR (CDCl₃, 270 MHz) δ 1.10-1.76 (m, 4H), 2.55 (td, J=2.4 and 12.2 Hz, 2H), 3.00-3.10 (m, 2H), 3.17 (t, J=6.2 Hz, 2H), 3.48 (s, 2H), 4.03 (d, J=4.9 Hz, 2H), 5.50 (br. s, 2H), 6.11-6.23 (m, 1H), 6.60 (d. J=8.8 Hz, 1H), 6.85-7.02 (m, 1H), 7.15 (dd, J=2.7 and 8.8 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H). ESI/MS m/e 325.2 (M⁺+H, C₁₅H₂₃ClN₄O₂).

Further, 4-[[(N-(2-amino-5-bromobenzoyl)glycyl)amino]methyl]piperidine was synthesized by using the corresponding starting material and reactants according to Reference Examples 33 and 34.951 mg, 64% (two steps); ESI/MS m/e 369.2 (M⁺+H, C₁₅H₂₁BrN₄O₂).

Example 1735 Synthesis of 4-[[(N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl)amino]methyl]-1-(4-chlorobenzyl)piperidine

Triethylamine (1.1 mL, 8 mmol), 2-(tert-butoxycarbonylamino)-4,5-difluorobenzoic acid (607 mg, 2.2 mmol), EDCI (422 mg, 2.2 mmol) and HOBt (337 mg, 2.2 mmol) were added to a dichloromethane (20 mL) solution of 1-(4-chlorobenzyl)-4-[(glycylamino)methyl]piperidine dihydrochloride (738 mg, 2 mmol), and the resulting mixture was stirred at room temperature for 14 hours. A 0.6 M aqueous solution of NaOH (50 mL) was then added to the mixture, and the obtained mixture was extracted with dichloromethane (3 times). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated to thereby provide 4-[[(N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl) glycyl)amino]methyl]-1-(4-chlorobenzyl)piperidine (1.01 g, 92%). ESI/MS m/e 551.3 (M⁺+H, C₂₇H₃₃ClF₂N₄O₄).

Moreover, 4-[[(N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl)amino]methyl]-1-(4 chlorobenzyl)piperidine was synthesized by using the corresponding starting material and reactants according to the above method. 3.03 g, 82%; ESI/MS m/e 583.2 (M⁺+H, C₂₈H₃₄ClF₃N₄O₄).

Reference Example 35 Synthesis of 4-[[(N-(2-amino-5-trifluoromethylbenzoyl) glycyl)amino]methyl]piperidine

A 5% formic acid/methanol solution (10 mL) of 1-(4-chlorobenzyl)-4-[[(N-(2-amino-5-trifluoromethylbenzoyl) glycyl)amino]methyl]piperidine (447 mg, 0.93 mmol) and Pd(OH) 2 (60 mg, 0.23 mmol) was stirred at 50° C. for 14 hours. The palladium catalyst was removed by filtration through Celite, and the filtrate was concentrated. A 1 M aqueous solution of NaOH (15 mL) was added to the resulting residue, and the obtained mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was purified by column chromatography (SiO₂ ethyl acetate/methanol/triethylamine=70:25:5) to thereby afford 4-[[(N-(2-amino-5-trifluoromethylbenzoyl)glycyl)amino]methyl]piperidine (284 mg, 86%). ESI/MS m/e 359.0 (M⁺+H, C₁₆H₂₁F₃N₄O₂). Furthermore, 4-[[(N-(2-amino-4,5-difluorobenzoyl)glycyl)amino]methyl]piperidine, 4-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethoxybenzoyl)glycyl]aminomethyl]piperidine and 4-[[(N-(2-(tert-butoxycarbonylamino)-5-trifluoromethoxybenzoyl)glycyl)amino]methyl]piperidine were synthesized by using the respective corresponding starting materials and reactants according to the above method. 4-[[(N-(2-amino-4,5-difluorobenzoyl)glycyl)amino]methyl]piperidine: 564 mg, 89%; ESI/MS m/e 327.2 (M⁺+H, C₁₅H₂₀F₂N₄O₂).

4-[[(N-(2-(tert-butoxycarbonylamino)-5-trifluoromethoxybenzoyl) glycyl)amino]methyl]piperidine: quantitative; ¹H NMR (CDCl₃, 400 MHz) δ 1.10-1.25 (m, 2H), 1.45-1.73 (m, 3H), 1.51 (s, 9H), 2.53-2.64 (m, 2H), 3.04-3.13 (m, 2H), 3.22 (t, J=6.3 Hz, 2H), 4.09 (d, J=4.6 Hz, 2H), 5.91 (br. s, 1H), 7.08 (br, s., 1H), 7.32 (d. J=9.0 Hz, 1H), 7.38 (s, 1H), 8.43 (d, J=9.0 Hz, 1H).

4-[[(N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl)amino]methyl]piperidine: 310 mg, 40%; ESI/MS m/e 427.3 (M⁺+H, C₂₀H₂₈F₂N₄O₄).

4-[[(N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl)amino]methyl]piperidine: 1.35 g, 57%; ESI/MS m/e 459.3 (M⁺+H, C₂₁H₂₉F₃N₄O₄).

Example 1736 Synthesis of 4-[[N-(2-amino-5-chlorobenzoyl)glycyl]aminomethyl]-1-(4-ethoxybenzyl)piperidine (Compd. No. 1429) and 1-(4-ethoxybenzyl)-4-[[N-(2-(4-ethoxybenzyl)amino-5-chlorobenzoyl)glycyl]aminomethyl]piperidine (Compd. No. 1433)

A methanol (0.4 mL) solution of sodium cyanoborohydride (140 mmol) was added to a mixture of 4-[[N-(2-amino-5-chlorobenzoyl)glycyl]aminomethyl]piperidine (0.10 mmol) with 4-ethoxybenzaldehyde (0.10 mmol), acetic acid (0.050 mL) and methanol (1.6 mL), and the resulting mixture was stirred at 60° C. for 14 hours. The obtained reaction mixture was loaded onto a Varian™ SCX column and washed with methanol (20 mL). The resulting products were eluted with a 2 M methanol solution of NH₃, concentrated and purified by preparative TLC (SiO₂, ethyl acetate/methanol) to thereby provide 4-[[N-(2-amino-5-chlorobenzoyl)glycyl]aminomethyl]-1-(4-ethoxybenzyl)piperidine (Compd. No. 1429) and 1-(4-ethoxybenzyl)-4-[[N-(2-(4-ethoxybenzyl)amino-5-chlorobenzoyl)glycyl]aminomethyl]piperidine (Compd. No. 1433).

Compd. No. 1429: 4.5 mg, 20%. The purity was determined by RPLC/MS (95%). ESI/MS m/e 459.2 (M⁺+H, C₂₄H₃₁ClN₄O₃).

Compd. No. 1433: 8.4 mg, 28%. The purity was determined by RPLC/MS (98%). ESI/MS m/e 593.2 (M⁺+H, C₃₃H₄₁ClN₄O₄).

Examples 1737 to 1779

The compounds used in the present invention were synthesized by using respective starting materials and reactants according to the method of Example 1736. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 36.

TABLE 36 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1737 1430 C₂₄H₂₉ClN₄O₄ 473.0 3.1 13 1738 1431 C₂₄H₃₁BrN₄O₃ 505.2 5.8 23 1739 1432 C₂₄H₂₉BrN₄O₄ 517.0 4.1 16 1740 1434 C₃₃H₄₁BrN₄O₆ 637.2 9.7 30 1741 1435 C₂₄H₃₁ClN₄O₂ 443.2 9.7 44 1742 1436 C₂₅H₃₃ClN₄O₂ 457.2 12.5 55 1743 1437 C₂₅H₃₃ClN₄O₃ 473.2 9.4 40 1744 1438 C₂₄H₃₁BrN₄O₂ 489.2 5.9 24 1745 1439 C₂₅H₃₃BrN₄O₂ 503.2 15.2 61 1746 1440 C₂₅H₃₃BrN₄O₃ 519.2 11.0 43 1747 1441 C₂₃H₂₉BrN₄O₂S 507.2 9.3 37 1748 1442 C₃₃H₄₁ClN₄O₂ 561.4 6.8 24 1749 1443 C₃₅H₄₅ClN₄O₂ 589.4 9.8 33 1750 1444 C₃₅H₄₅ClN₄O₄ 621.4 9.4 30 1751 1445 C₃₃H₄₁BrN₄O₂ 605.2 6.5 21 1752 1446 C₃₅H₄₅BrN₄O₂ 635.2 10.7 34 1753 1447 C₃₅H₄₅BrN₄O₄ 665.4 12.4 37 1754 1448 C₃₁H₃₇BrN₄O₂S₂ 643.2 7.6 24 1755 1457 C₂₄H₃₂ClN₅O₂ 458.2 4.5 20 1756 1458 C₂₃H₂₉ClN₄O₄ 461.2 6.0 26 1757 1459 C₂₄H₃₂BrN₅O₂ 504.0 6.8 27 1758 1460 C₂₃H₂₉BrN₄O₄ 505.0 8.0 32 1759 1461 C₃₁H₃₇ClN₄O₆ 597.2 5.9 20 1760 1462 C₃₁H₃₇BrN₄O₆ 643.2 6.0 19 1761 1514 C₂₆H₃₆ClN₅O₂ 486.2 5.5 23 1762 1515 C₂₃H₂₉ClN₄O₄ 463.0 5.8 25 1763 1516 C₂₆H₃₆BrN₅O₂ 530.2 4.2 16 1764 1517 C₂₃H₂₉BrN₄O₄ 505.0 6.5 26 1765 1518 C₃₁H₃₇ClN₄O₆ 597.2 4.3 14 1766 1519 C₃₁H₃₇BrN₄O₆ 641.2 5.3 17 1767 1570 C₂₃H₂₉ClN₄O₂S 461.0 2.7 12 1768 1571 C₃₁H₃₇ClN₄O₂S₂ 597.2 4.9 16 1769 1651 C₃₇H₄₉BrN₄O₂ 663.2 5.5 17 1770 1652 C₂₆H₃₅BrN₄O₂ 515.2 6.0 23 1771 1653 C₃₆H₄₅BrN₄O₂ 633.2 5.0 16 1772 1654 C₂₅H₃₃BrN₄O₂ 501.0 6.2 25 1773 1655 C₃₇H₄₉ClN₄O₂ 617.4 5.6 18 1774 1656 C₂₆H₃₅ClN₄O₂ 471.2 5.9 25 1775 1657 C₃₅H₄₅ClN₄O₂ 589.2 4.6 16 1776 1658 C₂₅H₃₃ClN₄O₂ 457.2 5.3 23 1777 1785 C₂₆H₃₃F₃N₄O₂ 491.2 4.7 12.8 1778 1786 C₂₅H₂₉F₃N₄O₃ 491.2 3.7 10.1 1779 1804 C₂₅H₃₂F₂N₄O₂ 459.2 3.3 9.6

Example 1780 Synthesis of 4-[[N-(2-amino-5-trifluoromethoxybenzoyl)glycyl]aminomethyl]-1-(4-isopropylbenzyl)piperidine (Compd. No. 1903)

Acetic acid (10 mL) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-5-(trifluoromethoxy)benzoyl)glycyl]aminomethyl]piperidine (0.050 mmol) with 4-isopropylbenzaldehyde (0.060 mmol), NaH₃CN (0.15 mmol) and methanol (1.3 mL), and the resulting mixture was stirred at 60° C. for 8 hours, cooled to room temperature, then loaded onto a Varian™ SCX column and washed with methanol (10 mL). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated. A 4 M dioxane solution of HCl (2 mL) was then added to the resulting residue, and the obtained solution was stirred at room temperature overnight, concentrated and then purified by preparative TLC to provide 4-[[N-(2-amino-5-trifluoromethoxybenzoyl)glycyl]aminomethyl]-1-(4-isopropylbenzyl)piperidine (Compd. No. 1903) (6.6 mg, 26%). The purity was determined by RPLC/MS (93%). ESI/MS m/e 507 (M⁺+H, C₂₆H₃₃F₃N₄O₃).

Examples 1781 to 1783

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1780. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 37.

TABLE 37 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1781 1904 C₂₆H₃₃F₃N₄O₃ 507 9.6 37.9 1782 1917 C₂₅H₃₁F₃N₄O₅ 525.2 1.2 3.1 1783 1918 C₂₄H₂₉F₃N₄O₄ 495.2 2.8 7.5

Example 1784 Synthesis of 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(5-bromo-2-ethoxybenzyl)piperidine (Compd. No. 2052)

NaBH₃CN (0.25 mmol) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl)]aminomethyl]piperidine (0.050 mmol) with 5-bromo-2-ethoxybenzaldehyde (0.15 mmol), methanol (1.2 mL) and acetic acid (0.030 mL). The resulting mixture was stirred at 50° for 13 hours, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (5 mL×3). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated. Dichloromethane (1 mL) and trifluoroacetic acid (0.50 mL) were added to the resulting residue, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated, and the residue was dissolved in methanol. The resulting solution was loaded onto a Varian™ SCX column and washed with methanol (5 mL). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL), concentrated and purified by preparative TLC (SiO₂, ethyl acetate/methanol=10:1) to provide 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(5-bromo-2-ethoxybenzyl)piperidine (Compd. No. 2052) (10.2 mg, 38%). The purity was determined by RPLC/MS (96%). ESI/MS m/e 539.2 (M⁺+H, C₂₄H₂₉BrF₂N₄O₃).

Examples 1785 to 1792

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1784. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 38.

TABLE 38 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1785 2053 C₃₀H₃₄F₂N₄O₄ 553.4 12.7 46 1786 2054 C₂₇H₃₀F₂N₄O₃ 497.2 13.7 55 1787 2055 C₂₃H₂₈F₂N₄O₄ 463.2 10.1 44 1788 2056 C₂₂H₂₄BrF₃N₄O₂ 515.2 7.7 30 1789 2057 C₂₃H₂₇BrF₂N₄O₃ 527.0 8.6 33 1790 2058 C₂₄H₃₀F₂N₄O₄ 477.2 6.4 27 1791 2059 C₂₈H₃₀F₂N₄O₃ 509.4 6.7 26 1792 2060 C₂₅H₃₂F₂N₄O₅ 507.2 7.2 28

Example 1793 Synthesis of 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3,4-diethoxybenzyl)-piperidine (Compd. No. 2065)

NaBH₃CN (0.25 mmol) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (0.050 mmol) with 3,4-diethoxybenzaldehyde (0.15 mol), methanol (1.2 mL) and acetic acid (0.050 mL), and the obtained mixture was stirred at 50° C. overnight, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated. Dichloromethane (2 mL) and phenyl isocyanate (0.10 mL) were added to the obtained residue, and the resulting mixture was stirred at room temperature for 1 hour, loaded onto a Varian™ SCX column and washed with methanol (5 mL). The obtained product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated. The residue was dissolved in methanol (0.25 mL); and a 4 M dioxane solution of HCl (0.125 mL) was added to the resulting solution. The obtained mixture was stirred at room temperature overnight and concentrated. The resulting residue was dissolved in methanol, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated to thereby afford 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3,4-diethoxybenzyl)piperidine (Compd. No. 2065) (21.2 mg, 84%). The purity was determined by RPLC/MS (97%). ESI/MS m/e 505.2 (M⁺+H, C₂₆H₃₄F₂N₄O₄).

Examples 1794 to 1808

The compounds used in the present invention were synthesized by using the respective corresponding raw materials and reactants according to the method of Example 1793. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 39.

TABLE 39 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1794 2061 C₂₃H₂₇F₃N₄O₂ 449.2 12.6 56 1795 2062 C₂₃H₂₇F₃N₄O₃ 465.2 19.7 85 1796 2063 C₂₅H₃₂F₂N₄O₄ 491.2 19.8 81 1797 2064 C₂₂H₂₄BrF₃N₄O₂ 515.2 17.5 68 1798 2066 C₂₉H₃₂F₂N₄O₃ 523.2 18.0 69 1799 2067 C₂₆H₃₄F₂N₄O₂ 473.2 21.9 93 1800 2068 C₂₂H₂₄ClF₃N₄O₂ 469.2 11.2 48 1801 2069 C₂₄H₃₀F₂N₄O₃ 461.4 20.2 88 1802 2070 C₂₃H₂₇BrF₂N₄O₃ 527.2 17.7 67 1803 2071 C₂₄H₃₀F₂N₄O₄ 477.2 10.9 46 1804 2072 C₂₅H₃₂F₂N₄O₃ 475.2 19.3 81 1805 2073 C₂₉H₃₂F₂N₄O₃ 523.2 22.8 87 1806 2074 C₂₉H₃₂F₂N₄O₄ 539.2 22.5 84 1807 2075 C₂₃H₂₇F₃N₄O₃ 465.2 14.9 64 1808 2076 C₂₂H₂₄F₄N₄O₂ 453.2 21.9 97

Example 1809 Synthesis of 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(2-hydroxy-3-methylbenzyl)piperidine (Compd. No. 2106)

NaBH₃CN (0.40 mmol) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (0.050 mmol) with 2-hydroxy-3-methylbenzaldehyde (0.25 mmol), methanol (1.0 mL) and acetic acid (0.040 mL). The resulting mixture was stirred at 50 overnight, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated. The residue was dissolved in ethyl acetate/methanol=5:1 (1 mL), loaded onto a Varian™ SCX column, eluted with ethyl acetate/methanol=5:1 (5 mL) and concentrated. The residue was dissolved in methanol (2 mL), and a 4 M dioxane solution of HCl (0.50 mL) was added to the resulting solution. The obtained mixture was stirred at room temperature overnight and concentrated. The residue was dissolved in methanol, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL), concentrated and purified by preparative TLC to thereby provide 4-[[N-(2-amino-4,5-difluorobenzoyl) glycyl]aminomethyl]-1-(2-hydroxy-3-methylbenzyl)piperidine (Compd. No. 2106). The purity was determined by RPLC/MS (97%). ESI/MS m/e 447.0 (M⁺+H, C₂₃H₂₈F₂N₄O₃).

Examples 1810 to 1823

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1809. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 40.

TABLE 40 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1810 2077 C₂₂H₂₅ClF₂N₄O₃ 467.2 3.7 16 1811 2078 C₂₄H₃₀F₂N₄O₄ 477.2 1.9  8 1812 2079 C₃₀H₃₄F₂N₄O₄ 553.4 4.8 17 1813 2080 C₂₂H₂₅ClF₂N₄O₃ 467.2 13.5 58 1814 2081 C₂₂H₂₅ClF₂N₄O₃ 467.2 13.8 59 1815 2082 C₂₃H₂₈F₂N₄O₄ 463.2 9.6 42 1816 2105 C₂₃H₂₈F₂N₄O₄ 463.2 ND ND 1817 2106 C₂₃H₂₈F₂N₄O₃ 447.0 ND ND 1818 2107 C₂₀H₂₃BrF₂N₄O₂S 503.1 ND ND 1819 2108 C₂₅H₂₈F₂N₄O₂S 487.2 ND ND 1820 2109 C₂₀H₂₃BrF₂N₄O₃ 487.0 ND ND 1821 2110 C₂₂H₂₈F₂N₄O₃ 435.1 ND ND 1822 2111 C₂₂H₂₄ClF₃N₄O₂ 469.0 ND ND 1823 2112 C₂₄H₂₉BrF₂N₄O₄ 557.0 ND ND Note: ND means “Not Determined”.

Example 1824 Synthesis of 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3-amino-4-methylbenzyl)piperidine (Compd. No. 2114)

NaBH₃CN (0.50 mmol) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (0.050 mmol) with 4-methyl-3-nitrobenzaldehyde (0.25 mmol), methanol (1.2 mL) and acetic acid (0.050 mL). The resulting mixture was stirred at 50° C. overnight, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated. The residue was dissolved in ethyl acetate/methanol=2:1 (2 mL), loaded onto a Varian™ Si column, eluted with ethyl acetate/methanol=2:1 (6 mL) and concentrated. The obtained residue was dissolved in methanol (1 mL), and a 4 M dioxane solution of HCl (0.50 mL) was added to the resulting solution. The obtained mixture was stirred at room temperature overnight and concentrated. The resulting residue was dissolved in methanol, loaded onto a Varian™ SCX column, washed with methanol (5 mL×2), then eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated to thereby afford 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(4-methyl-3-nitrobenzyl)piperidine.

A mixture of the resulting 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(4-methyl-3-nitrobenzyl)piperidine with a 5% palladium carbon (15 mg) and methanol (2 mL) was stirred at room temperature under a hydrogen atmosphere for 4 hours. The palladium catalyst was removed by filtration through Celite, and the filtrate was concentrated and purified by preparative TLC (SiO₂, ethyl acetate/methanol=3:1) to thereby provide 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3-amino-4-methylbenzyl)piperidine (Compd. No. 2114) (2.9 mg, 13%). The purity was determined by RPLC/MS (100%). ESI/MS m/e 446.1 (M⁺+H, C₂₃H₂₉F₂N₅O₂).

Example 1825 Synthesis of 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3-amino-4-methoxybenzyl)piperidine (Compd. No. 2113)

The title compound 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3-amino-4-methoxybenzyl)piperidine (Compd. No. 2113) was synthesized by using the corresponding starting material and reactants according to the method of Example 1824. 4.6 mg, 20% yield; ESI/MS m/e 462.2 (M⁺+H, C₂₃H₂₉F₂N₅O₃).

Example 1826 Synthesis of 1-(3-amino-4-hydroxybenzyl)-4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine

A methanol (3.2 mL) solution of NaBH₃CN (1.58 mmol) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (0.35 mmol) with 4-hydroxy-3-nitrobenzaldehyde-(1.22 mmol), methanol (3.8 mL) and acetic acid (0.175 mL), and the resulting mixture was stirred at 50° C. overnight, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated. The residue was dissolved in ethyl acetate/methanol=5:1, loaded onto a Varian™ Si column, eluted with ethyl acetate/methanol=5:1 (10 mL) and concentrated to thereby afford 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(4-hydroxy-3-nitrobenzyl)piperidine (175 mg, 87%).

A mixture of the resulting 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(4-hydroxy-3-nitrobenzyl)piperidine with a 10% palladium carbon (45 mg) and methanol (5 mL) was stirred at room temperature under a hydrogen atmosphere for 4 hours. The palladium catalyst was removed by filtration, and the filtrate was concentrated to provide 1-(3-amino-4-hydroxybenzyl)-4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (100 mg, 60%).

Example 1827 Synthesis of 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3-amino-4-hydroxybenzyl)piperidine (Compd. No. 2141)

A 4 M dioxane solution of HCl (0.50 mL) was added to a methanol (1 mL) solution of 1-(3-amino-4-hydroxybenzyl)-4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (20.0 mg, 0.035 mmol), and the resulting mixture was stirred at room temperature overnight and concentrated. The obtained residue was then dissolved in methanol, loaded onto a Varian™ SCX column, washed with methanol (5 mL×2), eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated to thereby afford 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3-amino-4-hydroxybenzyl)piperidine (Compd. No. 2141) (17.6 mg, quantitative). The purity was determined by RPLC/MS (85%). ESI/MS m/e 448.3 (M⁺+H, C₂₂H₂₇F₂N₅O₃).

Examples 1828 to 1831

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the methods of Examples 1826 and 1827. The obtained products, if necessary, were purified by preparative TLC to provide the objective compounds. Data of ESI/MS and yields (mg) and yields (%) in the final steps are collectively shown in Table 41.

TABLE 41 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1828 2140 C₂₃H₂₇F₂N₅O₄ 476.3 6.7 28.4 1829 2144 C₂₄H₃₀F₃N₅O₃ 494.2 18.7 82.0 1830 2145 C₂₃H₂₈F₃N₅O₃ 480.3 19.8 63.7 1831 2146 C₂₄H₂₈F₃N₅O₄ 508.3 13.5 81.7

Example 1832 Synthesis of 1-(3-amino-4-chlorobenzyl)-4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine

A methanol (1.3 mL) solution of NaBH₃CN (0.63 mmol) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (0.14 mmol) with 4-dichloro-3-nitrobenzaldehyde (0.50 mmol), methanol (1.5 mL) and acetic acid (0.070 mL). The resulting mixture was stirred at 50° C. overnight, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol. The obtained product was eluted with a 2 M methanol solution of NH₃ and concentrated. The residue was dissolved in ethyl acetate/methanol=5:1, loaded onto a Varian™ Si column, eluted with ethyl acetate/methanol=5:1 (6 mL) and concentrated to there by provide 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(4-chloro-3-nitrobenzyl)piperidine (44 mg, 53%). ESI/MS m/e 596.3 (M⁺+H).

A mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(4-chloro-3-nitrobenzyl)piperidine (121 mg, 0.20 mmol) with a 10% palladium carbon (85 mg), ethyl acetate (10 mL) and methanol (1 mL) was stirred at room temperature under a hydrogen atmosphere for 19 hours. The palladium catalyst was removed by filtration, and the filtrate was concentrated to thereby afford 1-(3-amino-4-chlorobenzyl)-4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (78 mg, 68%).

Example 1833 Synthesis of 1-(3-amino-4-chlorobenzyl)-4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (Compd. No. 2142)

The title compound 1-(3-amino-4-chlorobenzyl)-4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (Compd. No. 2142) was synthesized by using the corresponding starting material and reactants according to the method of Example 1827. 13.7 mg, 98%. The purity was determined by RPLC/MS (83%). ESI/MS m/e 466.2 (M⁺+H, C₂₂H₂₆ClF₂N₅O₂).

Example 1834 Synthesis of 1-(3-acetylamino-4-hydroxybenzyl)-4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (Compd. No. 2148).

A dichloromethane (0.12 mL) solution of acetic anhydride (0.12 mmol) was added to a mixture of 1-(3-amino-4-hydroxybenzyl)-4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (27 mg, 0.049 mmol) with a (piperidinomethyl)polystyrene (2.7 mmol/g, 60 mg, 0.15 mmol) and dichloromethane (2 mL), and the resulting mixture was stirred at room temperature for 3 hours. The mixture was loaded onto a Varian™ SCX column and washed with methanol. The obtained crude product was eluted with a 2 M methanol solution of NH₃ and concentrated. The residue was dissolved in ethyl acetate/methanol=5:1, loaded onto a Varian™ Si column, eluted with ethyl acetate/methanol=5:1 (6 mL) and concentrated to thereby provide 1-(3-acetylamino-4-hydroxybenzyl)-4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (30 mg, quantitative). ESI/MS m/e 590.4 (M⁺+H, C₂₉H₃₇N₅O₆).

A 4 M dioxane solution of HCl (0.50 mL) was added to a methanol (1 mL) solution of the 1-(3-acetylamino-4-hydroxybenzyl)-4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine obtained above, and the resulting solution was stirred at room temperature overnight and concentrated. The resulting residue was then dissolved in methanol, loaded onto a Varian™ SCX column, washed with methanol (5 mL×2), eluted with a 2 M methanol solution of NH₃ (5 mL), concentrated and then purified by preparative TLC (SiO₂, ethyl acetate/methanol=3:2) to thereby afford 1-(3-acetylamino-4-hydroxybenzyl)-4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (Compd. No. 2148) (2.3 mg, 9.2%). The purity was determined by RPLC/MS (98%). ESI/MS m/e 490.3 (M⁺+H, C₂₄H₂₉F₂N₅O₄).

Examples 1835 to 1839

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the methods of Examples 1826 and 1834. Data of ESI/MS and yields (mg) and yields (%) in the final steps are collectively shown in Table 42.

TABLE 42 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1835 2143 C₂₅H₂₉F₂N₅O₅ 518.3 4.8 45 1836 2147 C₂₅H₃₁F₂N₅O₄ 504.3 3.0 23 1837 2154 C₂₆H₃₂F₃N₅O₄ 536.4 4.1 66 1838 2155 C₂₅H₃₀F₃N₅O₄ 522.3 5.5 71 1839 2156 C₂₆H₃₀F₃N₅O₆ 550.3 7.0 78

Example 1840 Synthesis of 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3-methylamino-4-hydroxybenzyl)piperidine (Compd. No. 2160)

A methanol (0.2 mL) solution of NaBH₃CN (7.0 mg) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3-amino-4-hydroxy)piperidine (20.4 mg, 0.037 mmol) with a 37% HCHO solution (3.0 mg, 0.037 mmol), acetic acid (0.1 mL) and methanol (1.3 mL), and the resulting mixture was stirred at 60° C. overnight, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (5 mLX 2). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (8 mL) and concentrated to thereby provide 4-[[N-(2-tert-butoxycarbonylamino)-4,5- difluorobenzoyl]glycyl]aminomethyl]-1-(3-methylamino-4-hydroxybenzyl)piperidine.

A 4 M dioxane solution of HCl (1.0 mL) was added to a methanol (1.0 mL) solution of the 4-[[N-(2-tert-butoxycarbonylamino)-4,5-difluorobenzoyl]glycyl]aminomethyl]-1-(3-methylamino-4-hydroxybenzyl)piperidine obtained above, and the resulting mixture was stirred at room temperature for 3 hours and concentrated. The obtained residue was then dissolved in methanol (1 mL), loaded onto a Varian™ SCX column, washed with methanol (5 mL×2), eluted with a 2 M methanol solution of NH₃ (8 mL), concentrated and then purified by preparative TLC (SiO₂) to thereby afford 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3-methylamino-4-hydroxybenzyl)piperidine (Compd. No. 2160) (3.4 g, 20%). The purity was determined by RPLC/MS (96%). ESI/MS m/e 462.4 (M⁺+H, C₂₃H₂₉F₂N₅O₃).

Examples 1841 to 1844

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the methods of Examples 1826 and 1840. Data of ESI/MS and yields (mg) and yields (%) in the final steps are collectively shown in Table 43.

TABLE 43 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1841 2159 C₂₄H₃₁F₂N₅O₃ 476.3 7.6 48 1842 2161 C₂₃H₂₈ClF₂N₅O₂ 480.3 7.3 45 1843 2162 C₂₅H₃₂F₃N₅O₃ 508.4 6.0 24 1844 2163 C₂₄H₃₀F₃N₅O₃ 494.3 4.3 15

Example 1845 Synthesis of 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(benzo[c]furazan-5-yl)piperidine (Compd. No. 2130)

A mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (0.050 mmol) with 5-(bromomethyl)benzo[c]furazan (0.75 mL), a (piperidinomethyl)polystyrene (2.6-2.8 mmol/g, 60 mg, 0.15 mmol), methanol (0.2 mL), acetonitrile (1.0 mL) and chloroform (0.50 mL) was stirred at 50° C. overnight, cooled to room temperature, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated. Chloroform (1.5 mL) and phenyl isocyanate (0.075 mL) were added to the residue, and the resulting mixture was stirred at room temperature for 1 hour, loaded onto a Varian™ SCX column and washed with methanol (5 mLX 2). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated. The resulting residue was dissolved in methanol (1 mL), and a 4 M dioxane solution of HCl (0.50 ml) was added to the obtained solution. The resulting mixture was stirred at room temperature overnight and concentrated. The residue was then dissolved in methanol, loaded onto a Varian™ SCX column, washed with methanol (5 mL×2), eluted with a 2 M methanol solution of NH₃ (5 mL), concentrated and then purified by preparative TLC (SiO₂, ethyl acetate/methanol=5:1) to provide 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(benzo[c]furazan-5-yl)piperidine (Compd. No. 2130) (3.6 mg, 16%). The purity was determined by RPLC/MS (87%). ESI/MS m/e 459.3 (M⁺+H, C₂₂H₂₄F₂N₆O₃).

Example 1846 Synthesis of 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3,5-dimethylisoxazol-4-yl)piperidine (Compd. No. 2131)

The title compound 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3,5-dimethylisoxazol-4-yl)piperidine (Compd. No. 2131) was synthesized by using the corresponding starting material and reactants according to the method of Example 1845. 3.8 mg, 18% yield; ESI/MS m/e 436.2 (M⁺+H, C₂₁H₂₇F₂N₅O₃).

Example 1847 Synthesis of 4-[[N-(2-amino-5-chlorobenzoyl) glycyl]aminomethyl]-1-[4-(trifluoromethylthio)benzyl]piperidine (Compd. No. 1616)

A mixture of 4-[[N-(2-amino-5-chlorobenzoyl)glycyl]aminomethyl]piperidine (16.2 mg, 0.050 mmol) with 4-(trifluoromethylthio)benzyl chloride (20.3 mg, 0.075 mmol), acetonitrile (1.0 mL) and chloroform (0.56 mL) was stirred at 60° C. for 15 hours, cooled, then loaded onto a VarianM SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated to thereby afford 4-[[N-(2-amino-5-chlorobenzoyl) glycyl]aminomethyl]-1-[4-(trifluoromethylthio)benzyl]piperidine (Compd. No. 1616) (21.9 mg, 85%). The purity was determined by RPLC/MS (96%). ESI/MS m/e 545.2 (M⁺+H, C₂₃H₂₆ClF₃N₄O₂S).

Examples 1848 to 1868

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1847. The obtained products, if necessary, were purified by preparative TLC to provide the objective compounds. Data of ESI/MS and yields (mg) and yields (%) in the final steps are collectively shown in Table 44.

TABLE 44 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1848 1617 C₂₃H₂₆BrF₃N₄O₂S 559.0 21.0 75 1849 1777 C₂₃H₂₅Cl₂F₃N₄O₂ 517.0 16.3 63.0 1850 1778 C₂₄H₂₉F₃N₄O₂ 463.2 9.5 41.1 1851 1779 C₂₄H₂₇F₃N₄O₄ 493.2 12.7 51.6 1852 1780 C₂₃H₂₆BrF₃N₄O₂ 527.0 16.4 62.2 1853 1781 C₂₃H₂₇F₃N₄O₃ 465.2 10.0 28.7 1854 1782 C₂₅H₂₉F₃N₄O₂ 475.2 12.2 34.3 1855 1783 C₂₄H₂₆F₃N₅O₂ 474.2 17.2 48.4 1856 1784 C₂₃H₂₇F₃N₄O₂ 449.2 11.3 33.6 1857 1788 C₂₅H₃₁F₃N₄O₂ 477.2 10.0 42.0 1858 1789 C₂₄H₂₉F₃N₄O₃ 479.2 10.0 27.9 1859 1792 C₂₄H₃₀F₂N₄O₂ 445.2 5.9 26.5 1860 1793 C₂₂H₂₄Cl₂F₂N₄O₂ 485.2 9.2 37.9 1861 1794 C₂₃H₂₈F₂N₄O₂ 431.2 5.7 26.5 1862 1795 C₂₃H₂₆F₂N₄O₄ 461.2 6.0 26.1 1863 1796 C₂₂H₂₅BrF₂N₄O₂ 497.0 10.5 42.4 1864 1797 C₂₂H₂₆F₂N₄O₃ 433.2 3.5 16.2 1865 1798 C₂₃H₂₈F₂N₄O₃ 447.2 5.6 25.1 1866 1799 C₂₄H₂₈F₂N₄O₂ 443.2 5.5 24.9 1867 1800 C₂₃H₂₅F₂N₅O₂ 442.2 9.4 42.6 1868 1801 C₂₂H₂₆F₂N₄O₂ 417.2 6.5 31.2

Example 1869 Synthesis of 4-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]aminomethyl]-1-(4-bromobenzyl)piperidine (Compd. No. 1910)

A mixture of 4-[[N-(2-tert-butoxycarbonylamino)-5-trifluoromethoxybenzoyl]glycyl]aminomethyl]piperidine (0.050 mmol) with 4-bromobenzyl bromide (0.060 mmol), a piperidinomethylpolystyrene (60 mg), acetonitrile (0.8 mL) and chloroform (0.5 mL) was stirred at 60° C. for 12 hours, cooled, then loaded onto a Varian™ SCX column and washed with a 50% chloroform/methanol (10 mL) and methanol (10 mL). The obtained product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated. A 4 M 1, 4-dioxane solution of HCl (2 mL) was added to the resulting residue, and the obtained mixture was stirred at room temperature overnight, concentrated and then purified by preparative TLC to thereby provide 4-[[N-(2-amino-5-trifluoromethoxybenzoyl)glycyl]aminomethyl]-1-(4-bromobenzyl)piperidine (Compd. No. 1910) (6.5 mg, 24%). The purity was determined by RPLC/MS (96%). ESI/MS m/e 545 (M⁺+H, C₂₃H₂₆BrF₃N₄O₃).

Examples 1870 to 1873

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1869. Data of ESI/MS and yields (mg) and yields (%) in the final steps are collectively shown in Table 45.

TABLE 45 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1870 1911 C₂₃H₂₅Cl₂F₃N₄O₃ 533 10.6 39.7 1871 1912 C₂₃H₂₇F₃N₄O₄ 481 12.5 52.0 1872 1913 C₂₅H₃₁F₃N₄O₃ 493 7.5 30.5 1873 1914 C₂₄H₂₉F₃N₄O₃ 479 11.0 46.0

Example 1874 Synthesis of 4-[[N-(2-amino-5-trifluoromethylbenzoyl) glycyl]aminomethyl]-1-(benz[d]imidazol-5-yl)piperidine (Compd. No. 2186)

A mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]aminomethyl]piperidine (0.060 mmol) with 1-(tert-butoxycarbonyl)-6-(bromomethyl)benz[d]imidazole (15.6 mg, 0.050 mmol), a (piperidinomethyl)polystyrene (86 mg, 0.15 mmol) and acetonitrile (2 mL) was stirred at 50° C. for 3 hours and cooled to room temperature. Phenyl isocyanate (30 mg) was then added to the cooled mixture, and the resulting mixture was stirred at room temperature for 1 hour, loaded onto a Varian™ SCX column and washed with methanol (5 mL) and chloroform (5 mL). The obtained product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated.

The resulting substance was dissolved in methanol (1 mL), and a 4 M dioxane solution of HCl (1 mL) was added to the obtained solution. The resulting mixture was stirred at room temperature overnight, loaded onto a Varian™ SCX column, washed with methanol (5 mL) and dichloromethane. The resulting product was eluted with a 2 M methanol solution of NH₃ and concentrated. The obtained crude product was purified by preparative TLC (SiO₂, ethyl acetate/methanol=3:1) to thereby afford 4-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]aminomethyl]-1-(benz[d]imidazol-5-yl)piperidine (Compd. No. 2186) (1.9 mg, 7.8%). The purity was determined by RPLC/MS (100%). ESI/Ms m/e 489.4 (M⁺+H, C₂₄H₂₇F₃N₆O₂).

Example 1875 Synthesis of 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(benzo[c]thiadiazol-5-yl)piperidine (Compd. No. 2184)

Methanesulfonyl chloride (0.0042 mL) was added to a mixture of 5-(hydroxymethyl)benzo[c]thiadiazole (8.3 mg, 0.050 mmol) with a (piperidinomethyl)polystyrene (86 mg) and chloroform (1 mL), and the resulting mixture was stirred at room temperature for 1.5 hours. Acetonitrile (1 mL) and 4-[[(N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine were added to the mixture, and the resulting reaction mixture was stirred at 50° C. for 3 hours and cooled to room temperature. Phenyl isocyanate (30 mg) was then added to the cooled mixture, and the resulting mixture was stirred at room temperature for 1 hour, loaded onto a Varian™ SCX column and washed with methanol (5 mL) and chloroform (5 mL). The product was eluted with a 2 M methanol solution of NH₃ (3 mL) and concentrated. The resulting residue was dissolved in dichloromethane (1 mL), and a dichloromethane (1 mL) solution of chlorotrimethylsilane (1 M) and phenol (1 M) was added to the obtained solution. The resulting mixture was stirred at room temperature for 5 hours, then loaded onto a Varian™ SCX column and washed with methanol and dichloromethane. The obtained crude product was eluted with a 2 M methanol solution of NH₃ and purified by preparative TLC (SiO₂, ethyl acetate/methanol=3:1) to thereby provide 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(benzo[c]thiadiazol-5-yl)piperidine (Compd. No. 2184) (1.3 mg, 5.5%). The purity was determined by RPLC/MS (100%). ESI/MS m/e 475.2 (M⁺+H, C₂₂H₂₄F₂N₆O₂S).

Example 1876 Synthesis of 4-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]aminomethyl]-1-(benzo[c]thiadiazol-5-yl)piperidine (Compd. No. 2185)

4-[[N-(2-Amino-5-trifluoromethylbenzoyl)glycyl]aminomethyl]-1-(benzo[c]thiadiazol-5-yl)piperidine (Compd. No. 2185) was synthesized by using the corresponding starting material and reactants according to the method of Example 1875. 7.2 mg, 28% yield; ESI/MS m/e 507.4 (M⁺+H, C₂₃H₂₅F₃N₆O₂S).

Example 1877 Synthesis of 4-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]aminomethyl]-1-(2-amino-4-chlorobenzyl)piperidine (Compd. No. 1919)

A mixture of 4-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]aminomethyl]piperidine (0.050 mmol) with 4-chloro-2-nitrobenzyl chloride (0.050 mmol), a piperidinomethylpolystyrene (60 mg), acetonitrile (1.0 mL) and chloroform (0.7 mL) was stirred at 50° C. overnight, cooled, then loaded onto a Varian™ SCX column and washed with chloroform/methanol (10 mL) and methanol (10 mL). The obtained product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated. Ethanol (3 mL) and a 10% palladium carbon (15 mg) were added to the resulting residue, and the obtained mixture was stirred at room temperature under a hydrogen atmosphere for 1.5 hours and filtered. The filtrate was concentrated and then purified by preparative TLC to thereby afford 4-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]aminomethyl]-1-(2-amino-4-chlorobenzyl)piperidine (Compd. No. 1919) (5.1 mg, 14%). The purity was determined by RPLC/MS (90%). ¹H NMR (400 MHz, CDCl₃) δ 1.09-1.32 (m, 4H), 1.41-1.59 (m, 1H), 1.66 (d, J=12.5 Hz, 2H), 1.88 (t, J=11.5 Hz, 2H), 2.82 (d, J=11.5 Hz, H), 3.17 (t. J=6.5 Hz, 2H), 3.42 (s, 2H), 4.05 (d, J=3.5 Hz, 2H), 4.85 (br s, 1H), 5.92 (br s, 2H), 6.25-6.36 (m, 1H), 6.55-6.66 (m, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 7.26 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.68 (s, 1H); ESI/MS m/e 498.2 (M⁺+H, C₂₃H₂₇ClF₃N₅O₂).

Examples 1878 to 1879

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1877. Data of ESI/MS and yields (mg) and yields (%) in the final steps are collectively shown in Table 46.

TABLE 46 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1878 1920 C₂₂H₂₆ClF₂N₅O₂ 466.2 3.5 10.0 1879 1922 C₂₃H₂₇ClF₃N₅O₃ 514.2 1.2 3.1

Example 1880 Synthesis of 4-[[N-(2-amino-5-trifluoromethylbenzoyl)glycyl]aminomethyl]-1-(benz[d]oxazol-5-yl)piperidine (Compd. No. 2188)

Triethyl orthoformate (0.033 mL, 3.3 equivalents) and pyridinium p-toluenesulfonate (2 mg, 0.4 equivalent) were added to a THF (2 mL) solution of 1-(3-amino-4-hydroxybenzyl)-4-[[N-(2-(tert-butoxycarbonylamino)-5-trifluoromethylbenzoyl)glycyl]aminomethyl]piperidine (34.8 mg, 0.060 mL) synthesized according to the method of Example 1826. The resulting mixture was stirred under reflux overnight and cooled to room temperature. The obtained mixture was then concentrated, and the resulting residue was dissolved in ethyl acetate, loaded onto a Bond ElUt™ Si column, eluted with ethyl acetate/methanol=4:1 and concentrated.

The obtained residue was dissolved in ethyl acetate (1.5 mL), and a 4 M dioxane solution of HCl (0.5 mL) was added to the obtained solution. The resulting mixture was stirred at room temperature overnight, then adjusted to pH10 with a 5 M aqueous solution of NaOH and extracted with ethyl acetate. The extracts was concentrated and purified by preparative TLC (SiO₂, ethyl acetate/methanol=4:1) to thereby provide 4-[[N-(2-amino-5-trifluoromethylbenzoyl) glycyl]aminomethyl]-1-(benz[d]oxazol-5-yl)piperidine (Compd. No. 2188) (1.6 mg, 5%). The purity was determined by RPLC/MS (94%). ESI/MS m/e 490.3 (M⁺+H, C₂₄H₂₆F₃N₅O₃).

Example 1881 Synthesis of 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)piperidine (Compd. No. 2190)

Phenyl chloroformate (0.040 mL) was added to a mixture of 1-(3-amino-4-hydroxy)-4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (22 mg, 0.040 mmol) with NaHCO₃ (0.040 mmol), water (0.7 mL) and methanol (1.5 mL), and the resulting mixture was stirred at room temperature for 3 hours. A 1 M aqueous solution of NaOH (0.040 mL) was added, and the obtained mixture was further stirred for 1.5 hours. The mixture was then extracted with ethyl acetate, and the extracts was concentrated. The resulting residue was dissolved in methanol, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated. A dichloromethane (2 mL) solution of chlorotrimethylsilane (1 M) and phenol (1 M) was added to the obtained residue. The mixture was stirred at room temperature for 2 hours and concentrated. The resulting residue was dissolved in methanol, loaded onto a Varian™ SCX column and washed with methanol (5 mL×2). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL), concentrated and purified by preparative TLC (SiO₂, ethyl acetate/methanol=5:2) to thereby afford 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(2-oxo-2,3-dihydro-1,3-benzoxazol-5-yl)piperidine (Compd. No. 2190) (4.1 mg, 22%). The purity was determined by RPLC/MS (100%). ESI/MS m/e 474.2 (M⁺+H, C₂₃H₂₅F₂N₅O₄).

Examples 1882 to 1884

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 1881 (phenyl chlorothioformate was used in place of the phenyl chloroformate for synthesizing Compd. Nos. 2192 and 2193). Data of ESI/MS and yields (mg) and yields (%) in the final steps are collectively shown in Table 47.

TABLE 47 Compd. Yield Yield Example No. Chemical Formula ESI/MS m/e (mg) (%) 1882 2191 C₂₄H₂₆F₃N₅O₄ 506.3 3.1 10 1883 2192 C₂₃H₂₅F₂N₅O₃S 490.2 6.9 35 1884 2193 C₂₄H₂₆F₃N₅O₃S 522.2 3.6 11

Reference Example 36 4-[[N-(1-(9- fluorenylmethoxycarbonyl)piperidin-4-ylmethyl)carbamoylmethyl]aminomethyl]-3-methoxyphenyloxymethyl-polystyrene

Acetic acid (0.3 mL), sodium triacetoxyborohydride (1.92 g) and 4-formyl-3-(methoxyphenyloxymethyl)-polystyrene (1 mmol/g, 200 g) were added to a DMF (65 mL) solution of 1-(9-fluorenylmethoxycarbonyl)-4-(glycylaminomethyl)piperidine hydrochloride (10 mmol), and the resulting mixture was shaken for 2 hours and then filtered. The resin was washed with methanol, DMF, dichloromethane and methanol and dried to provide the objective substance.

Examples 1885 to 2000 Solid-phase synthesis of 4-aminomethylpiperidines

Diisopropylethylamine (3.6 mmol) was added to a mixture of the corresponding carboxylic acid (1.6 mmol) with HBTU (1.6 mmol) and DMF (6 mL), and the resulting mixture was shaken for 2 minutes. 4-[[N-(1-(9-Fluorenylmethoxycarbonyl)piperidin-4-ylmethyl)carbamoylmethyl]aminomethyl]-3-methoxyphenyloxymethyl-polystyrene (0.4 mmol) was added to the resulting mixture, and the obtained mixture was shaken for 1 hour and filtered. The resin was washed with dichloromethane and dried.

A mixture of NaBH(OAc)₃ (0.25 mmol) with acetic acid (0.025 mmol) and DMF was added to the obtained resin (0.05 mmol), and the corresponding aldehyde (2.5 mmol) was further added. The resulting mixture was shaken for 2 hours, then filtered and washed with methanol, a 10% DMF solution of diisopropylethylamine, DMF, dichloromethane and methanol. A mixture of the resin with water (0.050 mL) and trifluoroacetic acid (0.95 mL) was shaken for 1 hour and filtered. The resin was washed with dichloromethane and methanol. The filtrate and washings were combined and concentrated. The resulting residue was loaded onto a Varian™ SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated. The obtained product, if necessary, was purified by preparative TLC or HPLC to provide the objective compounds. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 48.

TABLE 48 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 1885 1923 C₂₃H₂₅BrF₃N₃O₂S 544 15.7 87 1886 1924 C₂₄H₂₈F₃N₃O₃S 496 14.6 89 1887 1925 C₂₃H₂₅F₄N₃O₂S 484 11.7 73 1888 1926 C₂₃H₂₄F₅N₃O₂S 502 13.9 84 1889 1927 C₂₃H₂₆F₃N₃O₃S 482 10.7 67 1890 1928 C₂₄H₂₆F₃N₃O₄S 510 14.3 85 1891 1929 C₂₆H₃₀F₃N₃O₂S 506 14.7 88 1892 1930 C₂₄H₂₈F₃N₃O₂S₂ 512 14.4 85 1893 1931 C₂₅H₃₀F₃N₃O₂S 494 14.3 88 1894 1932 C₂₅H₂₈F₃N₃O₃S 509 7.1* 35 1895 1933 C₂₅H₃₀F₃N₃O₂S 494 14.3 88 1896 1934 C₂₆H₃₂F₃N₃O₂S 509 14.4 86 1897 1935 C₂₃H₂₅F₃N₄O₄S 511 14.9 88 1898 1936 C₂₄H₂₈F₃N₃O₂S 480 13.3 84 1899 1937 C₂₆H₃₂F₃N₃O₂S 509 11.1 66 1900 1938 C₂₃H₂₇Br₂N₃O₂ 538 5.3* 25 1901 1939 C₂₄H₃₀BrN₃O₃ 488 5.0* 25 1902 1940 C₂₃H₂₇BrFN₃O₂ 476 4.9* 25 1903 1941 C₂₃H₂₆BrF₂N₃O₂ 494 6.1* 30 1904 1942 C₂₃H₂₈BrN₃O₃ 474 1.7* 9 1905 1943 C₂₄H₂₈BrN₃O₄ 502 6.6* 32 1906 1944 C₂₆H₃₂BrN₃O₂ 498 7.0* 35 1907 1945 C₂₄H₃₀BrN₃O₂S 504 11.1 67 1908 1946 C₂₈H₃₂BrN₃O₂ 488 3.2* 16 1909 1947 C₂₅H₃₀BrN₃O₃ 500 5.7 35 1910 1948 C₂₅H₃₂BrN₃O₂ 486 4.9* 25 1911 1949 C₂₆H₃₄BrN₃O₂ 500 6.7* 33 1912 1950 C₂₃H₂₇BrN₄O₄ 503 5.0* 25 1913 1951 C₂₄H₃₀BrN₃O₂ 472 5.1* 26 1914 1952 C₂₂H₂₄Br₂FN₃O₂ 542 14.9 83 1915 1953 C₂₃H₂₇BrFN₃O₃ 492 13.9 86 1916 1954 C₂₂H₂₄BrF₂N₃O₂ 480 12.5 79 1917 1955 C₂₂H₂₃BrF₃N₃O₂ 498 13.2 80 1918 1956 C₂₂H₂₅BrFN₃O₃ 478 7.0 44 1919 1957 C₂₃H₂₅BrFN₃O₄ 506 4.0* 20 1920 1958 C₂₅H₂₉BrFN₃O₂ 502 14.6 88 1921 1959 C₂₃H₂₇BrFN₃O₂S 508 13.1 78 1922 1960 C₂₄H₂₉BrFN₃O₂ 490 13.8 85 1923 1961 C₂₄H₂₇BrFN₃O₃ 504 2.7* 13 1924 1962 C₂₄H₂₉BrFN₃O₂ 490 12.7 78 1925 1963 C₂₅H₃₁BrFN₃O₂ 504 13.5 81 1926 1964 C₂₂H₂₄BrFN₄O₄ 507 14.8 88 1927 1965 C₂₃H₂₇BrFN₃O₂ 476 12.1 77 1928 1966 C₂₅H₃₁BrFN₃O₂ 504 13.4 80 1929 1967 C₂₂H₂₆BrFN₄O₂ 477 4.7* 20 1930 1968 C₂₃H₂₉FN₄O₃ 429 6.9* 32 1931 1969 C₂₂H₂₇FN₄O₃ 415 3.7* 17 1932 1970 C₂₃H₂₇FN₄O₄ 443 5.4* 24 1933 1971 C₂₅H₃₁FN₄O₂ 439 4.3* 20 1934 1972 C₂₃H₂₉FN₄O₂S 445 6.2* 28 1935 1973 C₂₄H₃₁FN₄O₂ 427 6.3* 29 1936 1974 C₂₄H₃₁FN₄O₂ 427 4.9* 23 1937 1975 C₂₂H₂₆FN₅O₄ 444 5.9* 27 1938 1976 C₂₃H₂₉FN₄O₂ 413 6.7* 32 1939 1977 C₂₃H₂₆FN₅O₂ 424 5.1* 24 1940 1978 C₂₅H₃₃FN₄O₂ 441 6.3* 29 1941 1979 C₂₅H₃₀F₂N₄O₂ 457 8.0* 35 1942 1980 C₂₄H₂₈F₂N₄O₃ 459 6.0* 26 1943 1981 C₂₂H₂₅F₂N₅O₄ 462 9.3* 41 1944 1982 C₂₃H₂₅F₂N₅O₂ 442 6.0* 27 1945 1983 C₂₅H₃₂F₂N₄O₂ 459 8.3* 37 1946 1984 C₂₂H₂₆BrIN₄O₂ 585 9.7* 36 1947 1985 C₂₃H₂₉IN₄O₃ 537 9.2* 36 1948 1986 C₂₂H₂₇IN₄O₃ 523 5.8* 23 1949 1987 C₂₃H₂₇IN₄O₄ 551 8.2* 32 1950 1988 C₂₅H₃₁IN₄O₂ 547 6.7* 26 1951 1989 C₂₃H₂₉IN₄O₂S 553 6.4* 25 1952 1990 C₂₄H₃₁IN₄O₂ 535 7.2* 29 1953 1991 C₂₄H₂₉IN₄O₃ 549 5.6* 22 1954 1992 C₂₄H₃₁IN₄O₂ 535 6.2* 25 1955 1993 C₂₂H₂₆IN₅O₄ 552 10.2* 40 1956 1994 C₂₃H₂₉IN₄O₂ 521 7.5* 30 1957 1995 C₂₃H₂₆IN₅O₂ 532 6.8* 27 1958 1996 C₂₅H₃₃IN₄O₂ 549 7.1* 28 1959 1997 C₂₅H₃₃IN₄O₂ 549 3.0* 12 1960 1998 C₂₂H₂₅BrClN₃O₂ 478 7.6* 39 1961 1999 C₂₃H₂₈ClN₃O₃ 430 7.0* 39 1962 2000 C₂₂H₂₅ClFN₃O₂ 418 14.1 102 1963 2001 C₂₂H₂₆ClN₃O₃ 416 6.3* 36 1964 2002 C₂₃H₂₆ClN₃O₄ 444 7.1* 39 1965 2003 C₂₅H₃₀ClN₃O₂ 440 15.3 105 1966 2004 C₂₃H₂₈ClN₃O₂S 446 8.4* 45 1967 2005 C₂₄H₃₀ClN₃O₂ 428 7.4* 41 1968 2006 C₂₄H₃₀ClN₃O₂ 428 13.8 98 1969 2007 C₂₂H₂₅ClN₄O₄ 445 16.0 109 1970 2008 C₂₃H₂₈ClN₃O₂ 414 14.1 103 1971 2009 C₂₃H₂₅ClN₄O₂ 425 14.8 106 1972 2010 C₂₅H₃₂ClN₃O₂ 442 14.5 99 1973 2011 C₂₅H₃₂ClN₃O₂ 442 14.5 99 1974 2012 C₂₂H₂₄Br₂ClN₃O₂ 558 12.8* 58 1975 2013 C₂₃H₂₇BrClN₃O₃ 508 8.6* 42 1976 2014 C₂₂H₂₅BrClN₃O₃ 494 6.0* 30 1977 2015 C₂₃H₂₅BrClN₃O₄ 522 8.4* 40 1978 2016 C₂₅H₂₉BrClN₃O₂ 518 17.6 103 1979 2017 C₂₃H₂₇BrClN₃O₂S 524 17.1 99 1980 2018 C₂₄H₂₉BrClN₃O₂ 506 14.7 88 1981 2019 C₂₄H₂₇BrClN₃O₃ 520 8.0* 38 1982 2020 C₂₄H₂₉BrClN₃O₂ 506 14.7 88 1983 2021 C₂₂H₂₄BrClN₄O₄ 523 12.0* 57 1984 2022 C₂₃H₂₇BrClN₃O₂ 492 8.5* 42 1985 2023 C₂₃H₂₄BrClN₄O₂ 503 6.3* 31 1986 2024 C₂₅H₃₁BrClN₃O₂ 520 9.6* 46 1987 2025 C₂₅H₃₁BrClN₃O₂ 520 15.0 87 1988 2026 C₂₂H₂₃BrClF₂N₃O₂ 514 15.8 93 1989 2027 C₂₂H₂₆Br₂N₄O₂ 537 10.7* 42 1990 2028 C₂₃H₂₉BrN₄O₃ 489 8.5* 36 1991 2029 C₂₂H₂₇BrN₄O₃ 475 7.5* 32 1992 2030 C₂₃H₂₇BrN₄O₄ 503 6.8* 28 1993 2031 C₂₅H₃₁BrN₄O₂ 499 6.2* 26 1994 2032 C₂₄H₂₉BrN₄O₃ 501 8.9* 37 1995 2033 C₂₄H₃₁BrN₄O₂ 487 9.1* 39 1996 2034 C₂₂H₂₆BrN₅O₄ 504 6.4* 26 1997 2035 C₂₃H₂₉BrN₄O₂ 473 6.5* 28 1998 2036 C₂₃H₂₆BrN₅O₂ 484 6.3* 27 1999 2037 C₂₅H₃₃BrN₄O₂ 501 5.4* 22 2000 2038 C₂₂H₂₅BrF₂N₄O₂ 495 5.4* 23 Note: *indicates “yield (mg) of trifluoroacetate”.

Example 2001 Synthesis of 1-(3-carbamoylbenzyl)-4-[[N-(3-trifluoromethyl)benzoyl]alycyl]aminomethyl]piperidine (Compd. No. 924)

EDCI (10.7 mg), 1-hydroxybenzotriazole hydrate (7.5 mg), triethylamine (15.4 mg), a 0.5 M dioxane solution of NH₃ (0.1 mL, 0.05 mmol) and DMF (0.5 mL) were added to a chloroform (2.5 mL) solution of 1-(3-carboxybenzoyl)-4-[[N-(3-trifluoromethyl)benzoyl]glycyl]aminomethyl]piperidine (19.4 mg, 0.041 mmol), and the resulting mixture was shaken at 25° C. for 20 hours and then washed with a 2 M aqueous solution of NaOH (2 X(2 mL) and brine (1 mL). The organic layer was filtered through a PTFE membrane filter, and the solvent was then removed under reduced pressure to provide 1-(3-carbamoylbenzyl)-4-[[N-(3-trifluoromethyl)benzoyl]glycyl]aminomethyl]piperidine (Compd. No. 924) as an off-white solid (17.9 mg, 92%). The purity was determined by RPLC/MS (89%). ESI/MS m/e 447.3 (M⁺+H, C₂₄H₂₇F₃N₄O₃).

Example 2002 Synthesis of 1-(4-carbamoylbenzyl)-4-[[N-(3-trifluoromethyl)benzoyl]glycyl]aminomethyl]piperidine (Compd. No. 925)

The Compd. No. 925 was synthesized by using the corresponding starting material and reactants according to the method of Example 2001. 14.2 mg, 72%. The purity was determined by RPLC/MS (86%). ESI/MS m/e 447 (M⁺+H, C₂₄H₂₇F₃N₄O₃).

Example 2003 Synthesis of 1-(4-aminobenzyl)-4-[[N-(3-trifluoromethyl)benzoyl]glycyl]aminomethyl]piperidine (Compd. No. 516)

An ethanol (3 mL) solution of 1-(4-nitrobenzyl)-4-[[N-(3-trifluoromethyl)benzoyl]glycyl]aminomethyl]piperidine (22.4 mg, 0.047 mmol) was hydrogenated in the presence of a 5% palladium carbon (10 mg) at 25° C. in a hydrogen atmosphere under 1 atm for 1 hour. The catalyst was removed by filtration, and washed with ethanol (5 mL). The filtrates were collected and concentrated to thereby afford 1-(4-aminobenzyl)-4-[[N-(3-trifluoromethyl)benzoyl]glycyl]aminomethyl]piperidine (Compd. No. 516) as an off-white solid (20.1 mg, 96%). The purity was determined by RPLC/MS (99%). ESI/MS m/e 449.1 (M⁺+H, C₂₃H₂₇F₃N₄O₂).

Examples 2004 to 2005

Compd. Nos. 517 and 518 were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 2003. Data of ESI/MS and yields (mg) and yields (%) in the final steps are collectively shown in Table 49.

TABLE 49 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 2004 517 C₂₃H₂₇F₃N₄O₂ 449 26.5 78 2005 518 C₂₃H₂₇F₃N₄O₂ 449 25.3 71

Example 2006 Synthesis of 1-[4-(benzoylamino)benzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 519)

EDCI (4.7 mg), 1-hydroxybenzotriazole hydrate (3.3 mg), triethylamine (2.5 mg) and benzoic acid (3.0 mg) were added to a dichloromethane (2.5 mL) solution of 1-(4-aminobenzyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (10.1 mg, 0.023 mmol), and the resulting mixture was shaken at 25° C. for 16 hours. The reaction mixture was washed with a 2 M aqueous solution of NaOH (2 mL×2) and brine (1 mL) and then filtered through a PTFE membrane filter. The solvent was evaporated under reduced pressure to thereby provide yellow oil. The obtained yellow oil was purified by preparative TLC (SiO₂, 10% methanol/dichloromethane) to afford 1-[4-(benzoylamino)benzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 519) as a colorless oil (4.6 mg, 36%). The purity was determined by RPLC/MS (99%). ESI/MS m/e 553.2 (M⁺+H, C₃₀H₃₁F₃N₄O₃).

Example 2007 Synthesis of 1-[4-(piperidinocarbonyl)benzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 1572)

Piperidine (0.048 mg), and a DMF (0.15 mL) solution of diisopropylcarbodiimide (0.45 mmol) and 1-hydroxybenzotriazole hydrate (0.45 mmol) were added to a DMF (1.0 mL) solution of 1-(4-carboxybenzyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (0.040 mmol), and the resulting mixture was shaken at room temperature for 17 hours, then loaded onto a Varian™ SCX column and washed with chloroform/methanol=1:1 (5 mL) and methanol (5 mL). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (5 mL) and concentrated to thereby provide 1-[4-(piperidinocarbonyl)benzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 0.1572) (14.3 mg, 66%). The purity was determined by RPLC/MS (99%). ESI/MS m/e 545 (M⁺+H, C₂₉H₃₅F₃N₄O₃).

Examples 2008 to 2015

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 2007. Data of ESI/MS and yields (mg) and yields (%) in the final steps are collectively shown in Table 50.

TABLE 50 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 2008 1573 C₃₁H₃₃F₃N₄O₄ 583 17.6 76 2009 1574 C₃₁H₃₃F₃N₄O₃ 567 18.8 83 2010 1575 C₃₀H₃₀ClF₃N₄O₃ 587 3.2 14 2011 1576 C₂₈H₃₃F₃N₄O₄ 547 21.1 97 2012 1577 C₂₆H₃₁F₃N₄O₄ 521 5.1 24 2013 1578 C₃₁H₃₃F₃N₄O₃ 567 16.9 75 2014 1579 C₃₁H₃₃F₃N₄O₃ 567 6.0 26 2015 1580 C₂₉H₃₅F₃N₄O₃ 545 15.1 69

Example 2016 Synthesis of 1-[4-(chloroformyl)benzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine

A mixture of 1-(4-carboxybenzyl)-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (240 mg) with thionyl chloride (1 mL) was stirred at room temperature for 12 hours, and the excess thionyl chloride was removed under reduced pressure to thereby afford 1-[4-(chloroformyl)benzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine. The resulting acid chloride was used without being further purified.

Example 2017 Synthesis of 1-[4-[N-(2-methoxyethyl)carbamoyl]benzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 1612)

A mixture of 1-[4-(chloroformyl)benzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (0.042 mmol) with 2-methoxyethylamine (3.8 mg, 0.050 mmol), a piperidinomethylpolystyrene (46 mg) and dichloromethane (1.5 mL) was stirred at room temperature for 17 hours. Water (0.020 mL) was then added to the mixture, and the resulting mixture was stirred for 30 minutes. Methanol (1 mL) was then added to the obtained mixture, and the resulting mixture was loaded onto a Varian™ SCX column and washed with methanol (10 mL). The obtained crude product was eluted with a 2 M methanol solution of NH₃ and concentrated to thereby provide 1-[4-[N-(2-methoxyethyl)carbamoyl]benzyl]-4-[[N-(3-(trifluoromethyl)benzoyl)glycyl]aminomethyl]piperidine (Compd. No. 1612) (26.7 mg, 100%). The purity was determined by RPLC/MS (92%). ESI/MS m/e 535.2 (M⁺+H, C₂₇H₃₃F₃N₄O₄).

Examples 2018 to 2020

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to Example 2017. The obtained products, if necessary, were purified by preparative TLC to afford the objective compounds. Data of ESI/MS and yields (mg) and yields (%) are collectively shown in Table 51.

TABLE 51 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 2018 1610 C₃₁H₃₀F₆N₄O₃ 621.2 4.4 14 2019 1611 C₃₀H₂₉Cl₂F₃N₄O₃ 621.2 35.7 Q 2020 1613 C₃₂H₃₅F₃N₄O₃ 581.2 29.9 Q Note: Q means “Quantitative”.

Example 2021 Synthesis of 4-[N-[5-bromo-2-(methylamino)benzoyl]glycyl]aminomethyl-1-(4-chlorobenzyl)piperidine (Compd. No. 1427)

A triethyl orthoformate (6.5 mL) solution of 4-[N-(2-amino-5-bromobenzoyl)glycyl]aminomethyl-1-(4-chlorobenzyl)piperidine (Compd. No. 1042) (50 mg, 0.10 mmol) was stirred at 150° C. for 17 hours and concentrated to thereby provide a yellow solid. Sodium borohydride (7.6 mg, 0.2 mmol) was added to an ethanol (3 mL) solution of the yellow solid, and the mixture was stirred at room temperature for 14 hours. The resulting white precipitate was dissolved in dichloromethane, and the obtained solution was washed with a 1 M aqueous solution of NaOH (2 mL). The organic layer was separated, dried over K₂CO₃, filtered and concentrated, and the obtained crude product was purified by column chromatography (SiO₂, 20% methanol/chloroform) to provide 4-[N-[5-bromo-2-(methylamino)benzoyl]glycyl]aminomethyl-1-(4-chlorobenzyl)piperidine (Compd. No. 1427) (40 mg, 80%). The purity was determined by RPLC/MS (100%). ESI/MS m/e 505 (M⁺+H, C₂₃H₂₈BrClF₆N₄O₂).

Example 2022 Synthesis of 4-[N-[5-bromo-2-(dimethylamino)benzoyl]glycyl]aminomethyl-1-(4-chlorobenzyl)piperidine (Compd. No. 1428)

Sodium cyanoborohydride (26 mg, 0.42 mmol) and acetic acid (14 mL) were added to a mixture of 4-[N-(2-amino-5-bromobenzoyl)glycyl]aminomethyl-1-(4-chlorobenzyl)piperidine (Compd. No. 1042) (67 mg, 0.14 mmol) with a 37% aqueous solution of formaldehyde (0.112 mL, 1.4 mmol), acetonitrile (2 mL) and methanol (1.5 mL), and the resulting mixture was stirred at 50° C. for 30 hours. A 1 M aqueous solution of NaOH and dichloromethane were added to the mixture. The aqueous layer was separated, and the organic layer was dried over K₂CO₃, filtered, concentrated and purified by column chromatography (SiO₂, 20% methanol/ethyl acetate) to afford 4-[N-[5-bromo-2-(dimethylamino)benzoyl]glycyl]aminomethyl-1-(4-chlorobenzyl)piperidine (Compd. No. 1428) (60 mg, 82%). The purity was determined by RPLC/MS (100%). ESI/MS m/e 523 (M⁺+H, C₂₄H₃₀BrClF₆N₄O₂).

Example 2023 Synthesis of 4-[[N-[5-bromo-2-(methylsulfonylamino)benzoyl]glycyl]aminomethyl]-1-(4-chlorobenzyl)piperidine (Compd. No. 1581)

A mixture of 4-[[N-[2-amino-5-bromobenzoyl]glycyl]aminomethyl]-1-(4-chlorobenzyl)piperidine (25 mg, 0.05 mmol) with methanesulfonyl chloride (0.0045 mL), triethylamine (0.026 mL) and dichloromethane (2 mL) was stirred at room temperature for 17 hours. The resulting reaction mixture was purified by column chromatography (SiO₂), loaded onto a Varian™ SAX column and washed with methanol (5 mL). The obtained crude product was eluted with a 0.1 M methanol solution of HCl (5 mL) and concentrated to thereby provide 4-[[N-[5-bromo-2-(methylsulfonylamino)benzoyl]glycyl]aminomethyl]-1-(4-chlorobenzyl)piperidine (Compd. No. 1581) (5.4 mg, 19%). ESI/MS m/e 573.0 (M⁺+H, C₂₃H₂₈BrClN₄O₄S).

Example 2024 Synthesis of 4-[[N-[5-bromo-2-(bis(methylsulfonyl)amino)benzoyl]glycyl]aminomethyl]-1-(4-chlorobenzyl)piperidine (Compd. No. 1582)

A mixture of 1-(4-chlorobenzyl)-4-[[N-[2-amino-5-bromobenzoyl]glycyl]aminomethyl]piperidine (57 mg, 0.10 mmol) with methanesulfonyl chloride (0.018 mL, 0.024 mmol), triethylamine (0.068 mL) and dichloromethane (2 mL) was stirred at room temperature for 8 hours. A 1 M aqueous solution of NaOH (1 mL) was added to the mixture, and the resulting mixture was extracted with dichloromethane (2 mL×3). The extracts were combined, dried over K₂CO₃, filtered, concentrated and purified by column chromatography (SiO₂) to afford 4-[[N-[5-bromo-2-(bis(methylsulfonyl)amino)benzoyl]glycyl]aminomethyl]-1-(4-chlorobenzyl)piperidine (Compd. No. 1582) (40 mg, 62%). ESI/MS m/e 651 (M⁺+H, C₂₄H₃₀BrClN₄O₆S₂).

Example 2025 Synthesis of 1-(4-chlorobenzyl)-1-methyl-4-[[N-[3-(trifluoromethyl)benzoyl]glycyl]aminomethyl]piperidinium iodide (methylammonium iodide of Compd. No. 461)

An acetonitrile (1.0 mL) solution of 4-[[N-[3-(trifluoromethyl)benzoyl]glycyl]aminomethyl]piperidine (30 mg, 0.087 mmol) and a (piperidinomethyl)polystyrene (80 mg, 2.7 mmol base/g resin) were added to a chloroform (1.0 mL) solution of 4-chlorobenzyl chloride (11.7 mg, 0.073 mmol), and the resulting mixture was stirred at 60° C. for 2 hours. Phenyl isocyanate (10.4 mg, 0.087 mmol) was then added to the reaction mixture cooled to room temperature, and the obtained mixture was stirred at 25° C. for 1 hour, then loaded onto a Varian™ SCX column and washed with methanol (20 mL). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (6 mL) and concentrated to thereby provide 1-(4-chlorobenzyl)-4-[[N-[3-(trifluoromethyl)benzoyl]glycyl]aminomethyl]piperidine as a colorless oil.

Methyl iodide (28 mg, 0.20 mmol) was added to an acetonitrile (2.0 mL) solution of 1-(4-chlorobenzyl)-4-[[N-[3-(trifluoromethyl)benzoyl]glycyl]aminomethyl]piperidine. The resulting reaction mixture was stirred at 70° C. for 4 hours. The solvent was removed under reduced pressure to provide 1-(4-chlorobenzyl)-1-methyl-4-[[N-[3-(trifluoromethyl)benzoyl]glycyl]aminomethyl]piperidinium iodide as yellow oil. (31.7 mg, 71%). The purity was determined by RPLC/MS (99%). ESI/MS m/e 482.1 (M⁺+H, C₂₄H₂₈ClF₃N₃O₂).

Example 2026 Synthesis of 1-(4-chlorobenzyl)-4-[N-methyl-N—[N-(3-(trifluoromethyl)benzoyl) lycyl]aminomethyl]piperidine (Compd. No. 520)

An aqueous solution of formaldehyde (108 mg, 1.33 mmol, 37 wt. %) was added to a 10% acetic acid/methanol (3 mL) solution of 1-(4-chlorobenzyl)-4-(aminomethyl)piperidine (318 mg, 1.33 mmol) and NaBH₃CN (668 mg), and the resulting mixture was stirred at 25° C. for 1 hour. The reaction mixture was loaded onto a Dowex™ 50W×2 column (10 mL) and washed with methanol (20 mL). The obtained crude product was eluted with a 2 M methanol solution of NH₃ (6 mL) and concentrated to thereby afford 1-(4-chlorobenzyl)-4-[(methylamino)methyl]piperidine as a colorless oil. The resulting oil was used without being purified.

EDCI (85 mg) and 1-hydroxybenzotriazole hydrate (60 mg) were added to a dichloromethane (4 mL) solution of 1-(4-chlorobenzyl)-4-[(methylamino)methyl]piperidine (111 mg, 0.44 mmol), and the resulting mixture was stirred at 25° C. for 1 hour, then washed with a 2 M aqueous solution of NaOH (2 mL×2) and filtered through a PTFE membrane filter. The solvent was subsequently removed under reduced pressure to provide a yellow oil, which was then purified by preparative TLC to afford 1-(4-chlorobenzyl)-4-[N-methyl-N—[N-(3-(trifluoromethyl)benzoyl) glycyl]aminomethyl]piperidine (Compd. No. 520) as an off-white oil (14.0 mg, 3.4%). The purity was determined by RPLC/MS (99%). ESI/MS m/e 482.1 (M⁺+H, C₂₄H₂₇ClF₃N₃O₂).

Reference Example 37 Synthesis of 3-aminohomopiperidine

A 1 M BH₃-THF solution (80 mL) was added to a THF (70 mL) solution of DL-α-amino-ε-caprolactam (2 g, 16 mmol), and the resulting mixture was refluxed for 3 hours. A 2 M hydrochloric acid (50 mL) was added, and the reaction mixture was further heated and refluxed for 1 hour and then cooled to 25° C. A 4 M NaOH solution was added to basicify the reaction mixture (pH10), and the resulting mixture was extracted with ethyl acetate (200 mL×3). The organic layers were combined, washed with a saturated aqueous NaHCO₃, dried (over MgSO₄) and concentrated to thereby provide the objective compound (990 mg, 54%). The obtained compounds was used without being purified.

Reference Example 38 Synthesis of 3-amino-1-(4-chlorobenzyl)homopiperidine

p-Chlorobenzyl chloride (463 mg, 2.9 mmol) and K₂CO₃ (828 g, 6 mmol) were added to an acetonitrile (45 mL) solution of 3-aminohomopiperidine (1.71 g, 15 mmol), and the resulting mixture was stirred at 70° C. with heating for 9 hours, cooled to 25° C. and concentrated to afford a yellow solid. The resulting residue was partitioned between H₂O (5 mL) and ethyl acetate (50 mL) and the aqueous layer was extracted with ethyl acetate (50 mL×2). The organic layers were combined, washed with brine (20 mL), dried (over MgSO₄) and concentrated. The obtained yellow oil was purified by column chromatography (SiO₂, 5-20% methanol/dichloromethane gradient elution) to afford the objective compounds as yellow oil (639 mg, 93%).

Example 2027 Synthesis of 1-(4-chlorobenzyl)-3-[(4-benzoylbutyryl)amino]homopiperidine (Comp d. No. 994)

EDCI (23 mg), HOBt (16.2 mg) and triethylamine (15.2 μL) were added to a chloroform (1 mL) solution of 3-amino-1-(4-chlorobenzyl)homopiperidine (24 mg, 0.10 mmol) and 4-benzoylbutyric acid (1.2 equivalents), and the resulting mixture was stirred at 25° C. for 16 hours. The reaction mixture was diluted with dichloromethane (0.5 mL), filtered through a PTFE membrane and concentrated to provide 1-(4-chlorobenzyl)-3-[(4-benzoylbutyryl)amino]homopiperidine (Compd. No. 994) (43 mg, 99%). The purity was determined by RPLC/MS (98%). ESI/MS m/e 413 (M⁺+H, C₂₄H₂₉ClN₂O₂).

Examples 2028 to 2042

The compounds used in the present invention were synthesized by using the respective corresponding starting materials and reactants according to the method of Example 2027. The obtained products, if necessary, were purified by chromatography (HPLC-Cl₈) to afford the objective compounds as TFA salts. Data of ESI/MS, yields (mg) and yields (%) are collectively shown in Table 52.

TABLE 52 Compd. Yield Yield Example No. Molecular Formula ESI/MS m/e (mg) (%) 2028 943 C₂₃H₂₅ClF₃N₃O₂ 468 6 28 2029 944 C₂₃H₂₈ClN₃O₂ 414 5 29 2030 945 C₂₂H₂₅ClN₄O₄ 445 6 30 2031 946 C₂₃H₂₇ClN₄O₄ 459 5 24 2032 947 C₂₅H₃₁ClN₂O₄ 459 4 20 2033 948 C₂₄H₂₉Cl₂N₃O₂ 462 6 32 2034 949 C₂₅H₃₂ClN₃O₂ 442 6 31 2035 988 C₂₃H₂₅ClF₃N₃O₂ 468 45  92 2036 989 C₂₃H₂₈ClN₃O₃ 430 44  97 2037 990 C₂₂H₂₆ClN₃O₂ 400 41  99 2038 991 C₂₃H₂₇ClN₂O₂ 399 41  97 2039 992 C₂₅H₃₁ClN₂O₄ 459 47  98 2040 993 C₂₅H₃₁ClN₂O₂ 427 44  98 2041 995 C₂₅H₃₁ClN₂O₃ 443 44  95 2042 996 C₂₄H₃₁ClN₄O₂ 443  5* 11 Note *indicates “yield (mg) of trifluoroacetate”.

Example 2043 Measurement of Inhibitory Activity of Test Compounds Against Binding of MIP-1 α to THP-1 Cells

THP-1 cells which are human monocytic leukemia cell line were suspended in an assay buffer [prepared by adding 0.1% of BSA and 25 mM of HEPES to RPMI-1640 (Gibco-BRL Co.) and adjusting the pH to 7.4] so as to provide 1×10⁷ cells/mL to thereby afford a cell suspension. A solution obtained by diluting the test compound with the assay buffer was used as a test compound solution. A solution prepared by diluting an iodine-labeled human MIP-1 α (DuPont NEN Co.) with the assay buffer so as to provided 250 nCi/mL was used as a labeled ligand solution. In a 96-well filter plate (Millipore Co.), were aliquoted 25 μL of the test compound solution, 25 μL of the labeled ligand solution and 50 μL of the cell suspension in the order mentioned for each well. The solutions were stirred (100 μL of the reaction solution) and then incubated at 18° C. for 1 hour.

After completing the reaction, the reaction solution was filtered through a filter, and the filter was washed with 200 μL of cold PBS twice (the reaction solution was filtered after adding 200 μL of the cold PBS). The filter was air-dried, and 25 μL of liquid scintillator was then added into each well to count the radioactivity retained by the cells on the filter using TopCount (Packard Instrument Co.).

The count when 100 ng of an unlabeled human MIP-1 α (Peprotech Co.) instead of the test compound was added was subtracted as nonspecific adsorption, and the count when the test compound was not added was taken as 100%. Thereby, the inhibitory activity of the test compound against binding of the human MIP-1 α to THP-1 cells was calculated. Inhibition ratio (%)=[1−(A−B)/(C−B)]×100 (wherein A is the count when the test compound is added; B is the count when 100 ng of the unlabeled human MIP-1 α is added; C is the count when only the [¹²⁵I]-labeled human MIP-1 α is added).

When the inhibitory activity of the cyclic amine derivatives which are active ingredients of the present invention was measured, for example, the following compounds respectively manifested an inhibitory activity of 20% to 50%, 50% to 80% and >80% at a concentration of 2 μM or 10 μM.

Compounds which manifested an inhibitory activity of 20% to 50% at a concentration of 10 μM:

Compd. Nos. 29, 37, 41, 45, 46, 47, 50, 82, 85, 107, 120, 134, 214, 217, 218, 220, 222, 225, 226, 227, 228, 229, 230, 231, 233, 234, 236, 237, 238, 333, 334, 335, 336, 338, 340, 342, 347, 348, 349, 350, 352, 357, 359, 361, 366, 372, 374, 375, 376, 380, 382, 383, 385, 470, 471, 472, 4731, 474, 483, 484, 488, 489, 491, 497, 499, 500, 502, 506, 508, 510, 514, 515, 518, 524, 543, 553, 554, 555, 556, 563, 571, 575, 576, 578, 579, 580, 583, 586, 587, 588, 590, 591, 592, 595, 596, 598, 603, 610, 611, 612, 614, 624, 625, 626, 629, 635, 638, 639, 640, 641, 642, 643, 644, 646, 647, 648, 649, 652, 653, 658, 659, 660, 665, 666, 669, 671, 675, 677, 679, 681, 682, 684, 691, 695, 696, 700, 702, 704, 706, 711, 712, 714, 717, 721, 723, 724, 726, 727, 728, 729, 731, 737, 739, 740, 741, 742, 744, 746, 765, 767, 772, 773, 774, 775, 776, 780, 781, 785, 786, 787, 788, 790, 791, 792, 793, 795, 796, 797, 798, 805, 806, 807, 810, 813, 820, 821, 822, 824, 825, 827, 829, 830, 833, 834, 837, 838, 844, 853, 855, 873, 877, 878, 880, 882, 887, 888, 891, 894, 901, 903, 904, 905, 911, 929, 932, 933, 935, 938, 940, 948, 993, 996, 1006, 1018, 1026, 1028, 1035, 1048, 1053, 1054, 1055, 1056, 1068, 1070, 1071, 1072, 1073, 1075, 1076, 1081, 1763 and 1764 Compounds which manifested an inhibitory activity of 50% to 80% at a concentration of 10 μM: Compd. Nos. 1, 2, 3, 4, 7, 13, 22, 23, 24, 25, 27, 31, 32, 38, 48, 83, 119, 121, 123, 131, 215, 216, 221, 235, 337, 351, 354, 358, 362, 363, 365, 367, 368, 369, 373, 378, 381, 384, 458, 459, 463, 465, 466, 467, 468, 478, 479, 480, 482, 485, 486, 487, 492, 493, 494, 495, 496, 498, 501, 503, 504, 507, 511, 512, 513, 520, 523, 527, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 545, 546, 547, 548, 549, 550, 551, 552, 558, 559, 560, 561, 562, 565, 567, 568, 569, 570, 572, 573, 574, 577, 581, 582, 594, 597, 599, 600, 602, 604, 606, 607, 608, 609, 613, 615, 616, 618, 619, 620, 621, 628, 630, 631, 632, 633, 634, 636, 637, 645, 651, 654, 655, 657, 661, 662, 664, 673, 674, 676, 678, 680, 683, 685, 687, 688, 689, 693, 703, 705, 707, 708, 709, 710, 713, 716, 718, 719, 720, 725, 730, 732, 733, 734, 735, 736, 749, 750, 751, 752, 753, 754, 756, 758, 760, 762, 763, 764, 766, 768, 769, 770, 771, 777, 778, 779, 784, 794, 799, 800, 802, 804, 808, 809, 811, 812, 815, 816, 819, 828, 831, 832, 835, 836, 839, 840, 845, 846, 847, 848, 850, 851, 854, 857, 858, 859, 860, 861, 862, 863, 865, 866, 867, 868, 872, 874, 876, 886, 899, 910, 942, 998, 1004, 1005, 1007, 1013, 1015, 1016, 1017, 1019, 1020, 1021, 1022, 1024, 1030, 1037, 1042, 1043, 1044, 1045, 1046, 1047, 1049, 1050, 1052, 1059, 1060, 1061, 1067, 1069, 1074, 1078, 1079, 1080 and 1766

Compounds which manifested an inhibitory activity of >80% at a concentration of 10 μM:

Compd. Nos. 461, 464, 469, 481, 490, 505, 509, 521, 526, 528, 544, 564, 566, 601, 605, 617, 622, 623, 627, 650, 656, 663, 668, 672, 686, 690, 692, 694, 715, 743, 747, 748, 755, 757, 759, 761, 782, 783, 803, 814, 817, 818, 826, 849, 856, 864, 869, 870, 871, 999, 1000, 1001, 1002, 1003, 1008, 1009, 1010, 1011, 1012, 1023, 1029, 1031, 1032, 1033, 1034, 1036, 1038, 1039, 1040, 1041, 1051, 1057, 1058, 1062, 1063; 1064, 1065, 1066, 1082 and 1083 Compounds which manifested an inhibitory activity of 20% to 50% at a concentration of 2 μM: Compd. Nos. 1042, 1043, 1244, 1245, 1416, 1435, 1436, 1438, 1441, 1480, 1570, 1583, 1584, 1589, 1590, 1594, 1595, 1601, 1660, 1672, 1687, 1724, 1779, 1780, 1787, 1795, 1796, 1798, 1799, 1802, 1893, 1894, 1898, 1900, 1915, 1919, 1920, 2092, 2096, 2098 and 2100

Compounds which manifested an inhibitory activity of 50% to 80% at a concentration of 2 μM:

Compd. Nos. 1190, 1414, 1600, 2091, 2094 and 2095 Compounds which manifested an inhibitory activity of >80% at a concentration of 2 M:

Compd. Nos. 2093, 2097, 2099, 2103 and 2104.

Example 2044 Measurement of Inhibitory Activity Against Binding of MCP-1 to THP-1 Cells

1. Preparation of Human MCP-1 Gene-Carrying Recombinant Baculovirus

Two kinds of DNA synthetic primers (5′-CACTCTAGACTCCAGCATGA-3′ (SEQ ID NO:1) and 5′-TAGCTGCAGATTCTTGGGTTG-3′) (SEQ ID NO:2) having restriction enzyme recognition sites applied on the basis of the known human MCP-1 gene sequence (see, for example, Yoshimura, T. et al. FEBS Letters 1989, 244, 487-493) were used to amplify a cDNA derived from human vascular endothelial cells (purchased from Kurabow) according to a PCR method. The amplified fragment was cleaved with restriction enzymes (PstI and XbaI) and then ligated into a transfer vector pVL1393 (Invitrogen Co.). The resulting vector was co-transfected with an infectious baculovirus into Sf-9 insect cells. Human MCP-1 gene recombinant baculoviruses were isolated from the obtained supernatant by a plaque assay method.

2. Synthesis of [¹²⁵I]-Labeled Human MCP-1 Expressed with Baculovirus

According to the method of Ishii, K. et al. (see Biochemical and Biophysical Research Communications, 1995, 206, 955-961), 5×10⁶ cells of Sf-9 insect cells were infected with 5×10⁷ PFU (plaque-forming units) of the above human MCP-1 gene recombinant baculoviruses and cultured in EX-CELL 401 medium for 7 days. The resulting culture supernatant was affinity purified by a heparin-Sepharose column (Pharmacia Co.) and then subjected to reverse phase HPLC (Vydac C18 column) to afford a purified human MCP-1. The protein labeling of the resulting purified human MCP-1 was requested for Amersham Co. to obtain a [¹²⁵I]-labeled human MCP-1 expressed with baculovirus (specific activity: 2000 Ci/mmol) prepared by the Bolten Hunter method. The resulting [¹²⁵I]-labeled human MCP-1 was used for the following tests.

3-1. Measurement of Inhibitory Activity Against Binding of [¹²⁵I]-Labeled Human MCP-1 Expressed with Baculovirus to THP-1 Cells (Method 1)

THP-1 cells which are human monocytic leukemia cell line were suspended in an assay buffer [prepared by adding 0.1% of BSA and 25 mM of HEPES to RPMI-1640 (Gibco-BRL Co.) and adjusting the pH to 7.4] so as to provide 1×10⁷ cells/mL to thereby afford a cell suspension. A solution obtained by diluting the test compound with the assay buffer was used as a test compound solution. A solution prepared by diluting the above [¹²⁵I]-labeled human MCP-1 expressed with baculovirus with the assay buffer so as to provide 1 μCi/mL was used as a lebeled ligand solution. In a 96-well filter plate (Millipore Co.), were aliquoted 25 μL of the test compound solution, 25 μL of the labeled ligand solution and 50 μL of the cell suspension in the order mentioned for each well. The solutions were stirred (100 μL of the reaction solution) and then incubated at 18° C. for 1 hour.

After completing the reaction, the reaction solution was filtered through a filter, and the filter was washed with 200 μL of cold PBS twice (the reaction solution was filtered after adding 200 μL of the cold PBS). The filter was air-dried and 25% L of liquid scintillator was then added into each well to count the radioactivity retained by the cells on the filter using TopCount (Packard Instrument Co.).

The count when 100 ng of the above human MCP-1 expressed with baculovirus (unlabeled) instead of the test compound was added was subtracted as nonspecific adsorption, and the count when the test compound was not added was taken as 100%. Thereby, the inhibitory activity of the test compound against binding of the human MCP-1 to THP-1 cells was calculated. Inhibition ratio (%)={1−(A−B)/(C−B)}×100 (wherein A is the count when the test compound is added; B is the count when 100 ng of the unlabeled human MCP-1 is added; C is the count when only the [¹²⁵I]-labeled human MCP-1 is added).

When the inhibitory activity of the cyclic amine derivatives which are active ingredients of the present invention was measured, for example, the following compounds respectively manifested an inhibitory activity of 20 to 50%, 50% to 80% and >80% at a concentration of 1 μM, 10 μM or 100 μM.

Compounds which manifested an inhibitory activity of 20% to 50% at a concentration of 100 μM:

Compd. Nos. 3, 6, 11, 15, 16, 19, 28, 44, 88, 92, 94, 104, 111, 112, 124, 125, 133, 219, 220, 224, 228, 236, 338, 343, 346, 347, 348, 349, 362, 363, 367, 368, 371, 373, 381, 618, 847, 849, 850, 866, 867, 869, 870, 871, 872 and 873 Compounds which manifested an inhibitory activity of 50% to 80% at a concentration of 100 μM: Compd. Nos. 1, 8, 10, 12, 18, 21, 26, 30, 33, 35, 39, 84, 89, 90, 91, 96, 97, 98, 99, 100, 101, 103, 106, 108, 109, 110, 116, 122, 126, 216, 218, 221, 225, 226, 231, 330, 332, 333, 334, 337, 341, 342, 350, 352, 354, 356, 359, 360, 361, 364, 366, 374, 375, 379, 382, 462, 463, 464, 557, 686, 840, 841, 842, 843, 844, 845, 846, 848, 862, 863, 864, 865, 868

Compounds which manifested an inhibitory activity of >80% at a concentration of 100 μM:

Compd. Nos. 2, 4, 5, 7, 13, 14, 17, 20, 22, 23, 24, 25, 27, 29, 31, 32, 34, 36, 38, 40, 41, 42, 43, 45, 46, 47, 48, 49, 50, 83, 85, 86, 95, 102, 105, 107, 113, 114, 115, 119, 120, 121, 123, 127, 128, 129, 130, 131, 132, 134, 214, 215, 217, 227, 237, 238, 331, 335, 336, 339, 340, 345, 351, 355, 357, 358, 383, 458, 459, 460, 466, 558, 851, 852, 861 and 874

Compounds which manifested an inhibitory activity of 20% to 50% at a concentration of 10 t M:

Compd. Nos. 12, 18, 30, 34, 40, 42, 43, 51, 52, 53, 54, 55, 56, 57, 59, 60, 64, 66, 75, 76, 77, 78, 79, 82, 89, 90, 97, 98, 102, 103, 116, 127, 128, 129, 130, 132, 135, 136, 140, 141, 144, 156, 157, 159, 160, 161, 162, 163, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 178, 179, 190, 191, 192, 195, 197, 200, 202, 203, 204, 205, 208, 233, 234, 235, 239, 240, 241, 242, 243, 245, 247, 249, 250, 255, 263, 264, 269, 274, 278, 279, 282, 306, 316, 317, 323, 324, 380, 404, 409, 433, 446, 448, 449, 451, 470, 471, 473, 476, 479, 486, 488, 489, 497, 498, 499, 501, 504, 507, 508, 509, 510, 512, 514, 516, 519, 527, 530, 532, 542, 545, 560, 563, 564, 565, 566, 568, 569, 572, 573, 574, 575, 578, 583, 584, 586, 587, 589, 590, 599, 600, 601, 603, 606, 612, 613, 620, 621, 622, 624, 625, 627, 629, 630, 632, 634, 636, 637, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 658, 678, 682, 687, 692, 694, 764, 775, 856, 857, 860, 881, 882, 883, 884, 890, 892, 899, 900, 903, 905, 907, 908, 911, 912, 916, 917, 921, 922, 923, 925, 927, 931, 932, 935, 939, 940, 968, 986, 1039, 1041, 1045, 1047, 1062, 1063 and 1083

Compounds which manifested an inhibitory activity of 50% to 80% at a concentration of 10 μM:

Compd. Nos. 7, 32, 36, 61, 62, 63, 65, 67, 69, 70, 71, 72, 73, 74, 81, 91, 105, 114, 121, 123, 134, 137, 138, 139, 146, 147, 148, 149, 151, 154, 165, 177, 232, 244, 248, 251, 252, 253, 256, 259, 261, 266, 267, 276, 286, 292, 293, 295, 301, 305, 307, 310, 314, 315, 320, 322, 328, 434, 435, 436, 437, 439, 440, 443, 447, 450, 452, 453, 454, 455, 456, 468, 469, 472, 474, 475, 477, 478, 480, 481, 482, 483, 485, 490, 493, 494, 500, 505, 511, 517, 520, 529, 534, 540, 543, 544, 548, 555, 556, 561, 562, 570, 576, 579, 611, 617, 853, 854, 855, 858, 859, 875, 877, 879, 880, 885, 886, 887, 888, 891, 894, 895, 904, 906, 909, 910, 913, 914, 918, 928, 930, 933, 937, 938, 945, 970, 1040, 1044 and 1046 Compounds which manifested an inhibitory activity of >80% at a concentration of 10 μM:

Compd. Nos. 31, 45, 46, 48, 58, 68, 80, 83, 113, 115, 142, 143, 145, 150, 152, 265, 268, 272, 275, 283, 285, 287, 288, 290, 291, 294, 296, 297, 302, 308, 309, 313, 321, 325, 326, 358, 438, 441, 442, 444, 445, 457, 466, 467, 484, 487, 491, 492, 495, 496, 503, 518, 537, 538, 547, 554, 876, 878, 919, 929 and 943 Compounds which manifested an inhibitory activity of 20% to 50% at a concentration of 1 μM:

Compd. Nos. 1118, 1121, 1136, 1143, 1146, 1158, 1159, 1167, 1170, 1359, 1361, 1362 and 1363

Compounds which manifested an inhibitory activity of 50% to 80% at a concentration of 1 μM:

Compd. Nos. 1133, 1134, 1137, 1141, 1156, 1161, 1162, 1163, 1164 and 1166

Compounds which manifested an inhibitory activity of >80% at a concentration of 1 μM:

Compd. No. 1147.

3-2. Measurement of Inhibitory Activity Against Binding of [¹²⁵I]-Labeled Human MCP-1 expressed with baculovirus to THP-1 cells (method 2)

THP-1 cells which are human monocytic leukemia cell line were suspended in an assay buffer (containing 50 mM of HEPES, 11.0 mM of CaCl₂, 5.0 mM of MgCl₂ and 0.5% of BSA at pH 7.4) so as to provide 1×10⁷ cells/mL to thereby obtain a cell suspension. A solution obtained by diluting the test compound with the assay buffer was used as a test compound solution. A solution prepared by diluting the above [¹²⁵I]-labeled human MCP-1 expressed with baculovirus with the assay buffer so as to provide 1 μCi/mL was used as a labeled ligand solution. In a 96-well filter plate (Millipore Co.), were aliquoted 25 μL of the test compound solution, 25 μL of the labeled ligand solution and 50 μL of the cell suspension in the order mentioned for each well. The solutions were stirred (100 μL of the reaction solution) and then incubated at 18° C. for 1 hour.

After completing the reaction, the reaction solution was filtered through a filter, and the filter was washed with 200 μL of cold PBS twice (the reaction solution was filtered after adding 200 μL of the cold PBS). The filter was air-dried, and 25% L of liquid scintillator was then added by into each well to count the radioactivity retained by the cells on the filter using TopCount (Packard Instrument Co.). The count when 100 ng of the above human MCP-1 expressed with baculovirus(unlabeled) instead of the test compound was added was subtracted as nonspecific adsorption, and the count when the test compound was not added was 100%. Thereby, the inhibitory activity of the test compound against binding of the human MCP-1 to THP-1 cells was calculated. Inhibition ratio (%)={1−(A−B)/(C−B)}×100 (wherein A is the count when the test compound is added; B is the count when 100 ng of the unlabeled human MCP-1 is added; C is the count when only the [¹²⁵I]-labeled human MCP-1 is added).

When the inhibitory activity of the cyclic amine derivatives which are the active ingredients of the present invention was measured, for example, the following compounds respectively manifested an inhibitory activity of 20% to 50%, 50% to 80% and >80% at a concentration of 0.2 μM, 1 μM or 10 μM.

Compounds which manifested an inhibitory activity of 20% to 50% at a concentration of 10 μM:

Compd. No. 1560

Compounds which manifested an inhibitory activity of 50% to 80% at a concentration of 10 μM:

Compd. No. 1550

Compounds which manifested an inhibitory activity of >80% at a concentration of 10 μM:

Compd. Nos. 541, 1042, 1043 and 1559

Compounds which Manifested an Inhibitory Activity of 20% to 50% at a Concentration of 1 μM:

Compd. Nos. 1098, 1100, 1101, 1104, 1105, 1109, 1110, 1116, 1174, 1175, 1176, 11178, 1187, 1188, 1189, 1197, 1198, 1199, 1200, 1201, 1202, 1209, 1210, 1211, 1212, 1222, 1225, 1229, 1230, 1237, 1238, 1243, 1250, 1259, 1261, 1265, 1266, 1272, 1277, 1282, 1294, 1299, 1302, 1307, 1315, 1318, 1319, 1320, 1329, 1330, 1335, 1336, 1337, 1343, 1344, 1353, 1355, 1356, 1357, 1358, 1368, 1372, 1385, 1386, 1392, 1400, 1413, 1422, 1423, 1425, 1426, 1429, 1430, 1432, 1437, 1440, 1445, 1446, 1447, 1448, 1450, 1452, 1453, 1455, 1458, 1459, 1461, 1463, 1464, 1466, 1468, 1469, 1470, 1471, 1474, 1479, 1482, 1485, 1507, 1508, 1510, 1511, 1512, 1513, 1514, 1515, 1516, 1518, 1519, 1521, 1522, 1524, 1535, 1538, 1540, 1542, 1544, 1571, 1573, 1574, 1575, 1576, 1577, 1578, 1579, 1580, 1581, 1582, 1585, 1587, 1598, 1602, 1603, 1604, 1609, 1611, 1612, 1613, 1614, 1615, 1616, 1617, 1618, 1622, 1627, 1630, 1643, 1646, 1662, 1669, 1716, 1717, 1723, 1728, 1731, 1733, 1736, 1739, 1740, 1747, 1750, 1755, 1757, 1758, 1759, 1760, 1761, 1762, 1769, 1770, 1771, 1772, 1773, 1774, 1777, 1783, 1784, 1785, 1791, 1793, 1904, 1911, 1917, 2057, 2061, 2063, 2064, 2065, 2066, 2067, 2068, 2069, 2071, 2072, 2073, 2074, 2075, 2076, 2080, 2081, 2082, 2110, 2112, 2123, 2130, 2131, 2139, 2170, 2180, 2181, 2182, 2212, 2216, 2217, 2219, 2220, 2222, 2224, 2225, 2228, 2247, 2253, 2254, 2255, 2256 and 2257

Compounds which manifested an inhibitory activity of 50% to 80% at a concentration of 1 μM:

Compd. Nos. 37, 298, 318, 1084, 1091, 1103, 1106, 1108, 1111, 1113, 1114, 1115, 1138, 1142, 1165, 1179, 1190, 1192, 1193, 1195, 1196, 1204, 1205, 1206, 1207, 1208, 1245, 1246, 1255, 1257, 1258, 1262, 1263, 1293, 1300, 1342, 1351, 1352, 1354, 1370, 1371, 1373, 1375, 1377, 1378, 1380, 1381, 1383, 1384, 1391, 1411, 1412, 1414, 1417, 1418, 1419, 1421, 1424, 1431, 1436, 1439, 1449, 1454, 1456, 1457, 1460, 1462, 1472, 1473, 1487, 1502, 1504, 1506, 1517, 1525, 1526, 1527, 1529, 1530, 1531, 1532, 1533, 1534, 1536, 1537, 1539, 1541, 1545, 1593, 1600, 1601, 1606, 1608, 1619, 1620, 1621, 1623, 1624, 1625, 1626, 1628, 1629, 1645, 1650, 1654, 1658, 1663, 1664, 1665, 1670, 1671, 1672, 1673, 1675, 1678, 1679, 1681, 1684, 1687, 1688, 1689, 1690, 1711, 1712, 1714, 1718, 1722, 1725, 1726, 1727, 1729, 1730, 1732, 1734, 1735, 1737, 1741, 1742, 1743, 1744, 1745, 1746, 1748, 1751, 1753, 1754, 1756, 1779, 1781, 1782, 1786, 1788, 1789, 1790, 1792, 1795, 1797, 1798, 1800, 1801, 1804, 1848, 1862, 1883, 1885, 1886, 1887, 1889, 1893, 1894, 1903, 1905, 1910, 1912, 1913, 1914, 1918, 1922, 1976, 1985, 2027, 2035, 2062, 2083, 2084, 2088, 2089, 2090, 2111, 2124, 2125, 2126, 2135, 2167, 2171, 2175, 2211, 2221, 2226, 2231 and 2240 Compounds which manifested an inhibitory activity of >80% at a concentration of 1 μM: Compd. Nos. 299, 311, 312, 329, 1042, 1043, 1085, 1119, 1191, 1203, 1220, 1228, 1236, 1244, 1256, 1288, 1295, 1308, 1310, 1376, 1382, 1393, 1395, 1415, 1416, 1420, 1435, 1438, 1441, 1480, 1481, 1570, 1583, 1584, 1589, 1590, 1594, 1595, 1607, 1634, 1660, 1661, 1666, 1668, 1695, 1696, 1697, 1698, 1699, 1701, 1702, 1703, 1704, 1705, 1706, 1707, 1708, 1709, 1713, 1724, 1749, 1752, 1775, 1776, 1778, 1780, 1787, 1794, 1796, 1799, 1802, 1803, 1841, 1869, 1870, 1871, 1872, 1876, 1877, 1892, 1896, 1897, 1898, 1899, 1900, 1901, 1902,1906, 1907, 1908, 1909, 1915, 1916, 1919, 1920, 1921, 2085, 2086, 2087, 2113, 2114, 2118, 2119, 2120, 2121, 2122, 2127, 2128, 2129, 2132, 2133, 2136, 2137, 2138, 2159, 2161, 2162, 2169, 2172, 2178, 2179, 2187, 2189, 2193, 2210, 2213, 2214, 2215, 2218, 2227, 2229, 2230, 2232, 2233, 2235, 2236, 2237, 2238, 2241, 2242, 2243, 2244, 2245, 2246, 2248, 2249, 2250, 2251 and 2252

Compounds which manifested an inhibitory activity of 20% to 50% at a concentration of 2 μM:

Compd. Nos. 1680, 1682, 1686, 1691, 1694, 1700, 1805, 1810, 1811, 1812, 1813, 1815, 1816, 1817, 1818, 1819, 1820, 1824, 1825, 1826, 1827, 1828, 1832, 1833, 1834, 1835, 1836, 839, 1840, 1842, 1843, 1851, 1852, 1853, 1854, 1855, 1856, 1858, 1859, 1860, 1863, 1864, 1865, 1866, 1868, 1874, 1878, 1879, 1880, 1888, 1890, 1891, 1895, 1926, 1927, 1928, 1929, 1930, 1934, 1935, 1937, 1945, 1946, 1951, 1952, 1953, 1954, 1959, 1960, 1961, 1962, 1966, 1969, 1970, 1971, 1972, 1973, 1977, 1978, 1979, 1980, 1981, 1985, 2014, 2027, 2028, 2033, 2035, 2039, 2040, 2041, 2042, 2044, 2045 and 2046

Compounds which manifested an inhibitory activity of 50% to 80% at a concentration of 0.2 g M:

Compd. Nos. 1677, 1678, 1679, 1681, 1687, 1688, 1689, 1690, 1695, 1697, 1808, 1809, 1841, 1848, 1861, 1862, 1869, 1870, 1871, 1872, 1873, 1876, 1877, 1883, 1884, 1885, 1886, 1887, 1889, 1893, 1894 and 1976 Compounds which manifested an inhibitory activity of >80% at a concentration of 0.2 M: Compd. Nos. 1696 and 1892.

Example 2045 Measurement of Inhibitory Activity Against Binding of MCP-1 to Cells Expressing the MCP-1 Receptor (Evaluation using [¹²⁵I]-Labeled Human MCP-1)

1. Obtaining of Cells Expressing the MCP-1 Receptor

An MCP-1 receptor cDNA fragment obtained by Yamagami, S. et al. (see Biochemical and Biophysical Research Communications, 1994, 202, 1156-1162) was cloned into an NotI site of an expression plasmid pCEP-4 (Invitrogen Co.), and the resulting plasmid was transfected into human kidney epithelial cell line 293-EBNA with a Lipofectamine reagent (Gibco-BRL Co.) and the cells were cultured in the presence of a selective agent (Hygromycin) to provide a stably expressing transfactant line. The expression of the receptor was confirmed by binding properties of the [¹²⁵I]-labeled human MCP-1.

2. Measurement of Inhibitory Activity Against Binding of [¹²⁵I]-Labeled Human MCP-1 Expressed with Baculovirus to MCP-1 Receptor-Expressing Cells

The MCP-1 receptor-expressing cells on a tissue culture dish were scraped using a cell scraper and suspended in the assay buffer [prepared by adding 0.1% of BSA and 25 mM of HEPES to D-MEM (Gibco-BRL Co.) and adjusting the pH to 7.4] to thereby provide a cell suspension of a concentration 6×10⁶ cells/ml. The same subsequent procedures were performed as described in Example 2044.

When the inhibitory activity of the cyclic amine derivatives, which were the active ingredients of the present invention, was measured, the inhibitory activity of the representative compounds in the Example was approximately the same as that described in Example 2044.

Example 2046 Measurement of Inhibitory Activity Against Cell Chemotaxis

In order to determine the inhibitory activity of the compounds according to the present invention against the cell chemotaxis, human monocytic leukemia cell line THP-1 was used as chemotactic cells according to the method of Fall et al. (J. Immunol. Methods, 1980, 33, 239-247) to determine the cell chemotaxis caused by monocyte chemotactic factor MCP-1 as follows: Namely, 2×10⁶ cells/mL of the THP-1 cells [suspended in RPMI-1640 (Flow Laboratories Co.) 10% FCS] were placed in the upper chamber (200 μL) of a 96-well microchemotaxis chamber (Neuroprobe®), and human recombinant MCP-1 (Peprotech Co.) diluted with the same solution so as to provide the final concentration of 20 ng/mL was placed in the lower chamber (35 μL). A polycarbonate filter (PVP-free, Neuroprobe®) was placed between the two chambers. These were incubated in the presence of 5% of CO₂ at 37° C. for 2 hours.

The filter was removed, and the cells which had migrated to the undersurface of the filter were immobilized, stained using Diff Quick (Kokusai Shiyaku Co.) and then measured at a measuring wavelength of 550 nm using a plate reader (Molecular Device Co.) to determine the means of 3 wells. Thereby, the indication of the number of cells migrated was obtained. The test compound together with the THP-1 cells was added to the upper chamber at various concentrations to determine the inhibitory activity against cell chemotaxis [degree of inhibition: IC₅₀ (μM)]. The degree of inhibition was defined as {(number of cells migrated with MCP-1 when no test compound was added to the upper chamber)−(number of cells migrated when no MCP-1 was added to the lower chamber)=100%}, and the concentration of the compound manifested 50% of the inhibition was designated as IC₅₀.

When the inhibitory activity of the cyclic amine derivatives which are the active ingredients of the present invention was determined, for example, the IC₅₀ value of the following compounds was 0.1 μM or below.

Examples of compounds which manifested an IC₅₀ value of 0.1 μM or below:

Compd. Nos. 4, 37, 298, 299, 311, 312, 318, 329, 461, 886, 909, 1042, 1043, 1085, 1119, 1138, 1142, 1165, 1179, 1191, 1203, 1205, 1220, 1228, 1236, 1244, 1245, 1256, 1288, 1293, 1295, 1308, 1310, 1352, 1376, 1382, 1393, 1395, 1416, 1420, 1435, 1436, 1438, 1441, 1480, 1531, 1532, 1570, 1583, 1584, 1589, 1590, 1594, 1595, 1600, 1601, 1607, 1660, 1661, 1664, 1666, 1668, 1698, 1699, 1701, 1702, 1703, 1704, 1706, 1707, 1708, 1709, 1713, 1775, 1776, 1778, 1779, 1787, 1794, 1796, 1799, 1802, 1803, 1896, 1898, 1899, 1900, 1901, 1902, 1906, 1907, 1908, 1909, 1915, 1916, 1919, 1920, 1921, 2087, 2114, 2128, 2129, 2132, 2137, 2141, 2144, 2157, 2158, 2189, 2213, 2214, 2235, 2236, 2241, 2242, 2244, 2249, 2250 and 2251.

The results in Examples 2043, 2044. 2045 and 2046 definitely show that the compounds of the present invention as a receptor antagonist of chemokines such as MIP-1 α and/or MCP-1 have the inhibitory activity against actions of the chemokines on target cells.

Example 2047 Studies on Inhibitors Effects on Collagen-Induced Arthritis in Mice

Collagen-induced arthritis in mice was induced according to the method of Kato et al. (Arthritis in mice induced by a single immunization with collagen, Ann. Rheum. Dis., 55, 535-539, 1996).

1. Method

Type II collagen derived from a bovine joint (Collagen Gijutsu-kenshukai) was emulsified with an volume of a Freund's complete adjuvant (ICN Immunobiologicals) to prepare a homogeneous emulsion. An ultrasonic homogenizer (Taitec) was used to prepare the emulsion. The emulsion (in a dose of 0.15 mg/0.1 mL/body) was intracutaniously injected into the base of the tail of DBA/1 mice (Charles River, Japan Inc.) by using a glass syringe for tuberculin and a 27G injection needle.

The test compound was suspended in a 0.5% aqueous solution of sodium carboxymethyl cellulose (CMC, Wako Pure Chemical Industries, Ltd.) with a mortar to prepare a prescribed administration suspension, which was orally administered from the date after the administration of the emulsion.

The experimental groups are three of a group administered with 0.5% of CMC (hereinafter referred to as the control group) and groups administered with 30 mg/kg or 100 mg/kg of the test compound. The solution or the test compound was administered once a day, and the number of animals in each group was 16.

2. Evaluation of Arthritis

The degree of joint swelling was scored for each digital joint of four limbs after the passage of 12 weeks from the administration of the emulsion according to the method of Abe (immunotherapy in arthritis model, Japanese Journal of Inflammations 12, 417-422, 1992). Each limb was scored in four grades of scores 0 to 3, and the maximum was score 12.

3. Actions on Synovial Hyperlasia, Chondrolysis of Articular Cartilages and Osteolysis of Subchondral Bone

After observing the arthritis scores, the right hindlimbs were removed. After embedding in paraffin, thin slice of knee joint were prepared and subjected to hematoxylin-eosin staining to evaluate actions on synovial hyperplasia, chondrolysis, destruction of articular cartilages and osteolysis of subchondral bone according to a conventional method. The rating was carried out in five grades of scores 0 to 4 for each measurement item.

4. Results of evaluation

The category type Dunnett's tests compared with the control group were carried out, and a p value of 0.05 or below was taken as significantly different.

The following graphs are expressed as mean ±standard deviation (SD). FIG. 1 illustrates the results of arthritis when Compd. No. 1583 was orally administered for 12 weeks. The group administered with Compd. No. 1583 significantly inhibited arthritis scores as compared with the control group.

FIGS. 2 to 4 respectively illustrates results of Compd. No. 1583 on synovial hyperplasia, chondrolysis of articular cartilages and osteolysis of subchondral bone. Compd. No. 1583 significantly inhibited for all the evaluation items.

Example 2048 Studies on Inhibitory Effects on Collagen-Induced Arthritis in Rats

Collagen-induced arthritis in rats was induced by modifying the method of Trentham et al. (Autoimmunity to type II collagen: an experimental model of arthritis. J. Exp. Med., 146, 857-68 (1977) as follows:

1. Method

Type II collagen derived from a bovine joint (Collagen Gijutsu-kenshukai) and muramyl dipeptide (CHEMICON International) were mixed with an Freund's incomplete adjuvant so as to provide each final concentration of 0.08% and 0.02% to thereby prepare a homogenous emulsion. The resulting emulsion was prepared by vigorous stirring at 4° C. in two glass syringes connected with a connector. One mL of the emulsion was injected intradermally in 10 sites on the back of Lewis female rats (Charles River Japan, Inc., 6-weeks-old) by using a glass syringe for tuberculin and a 26G injection needle. After one week, the base of the tail was additionally immunized (boosted) intradermally with 0.1 mL of the emulsion prepared by the same method as described above.

The test compound was suspended in a 0.5% aqueous solution of sodium carboxymethylcellulose (CMC, Wako Pure Chemical Industries, Ltd.) with a mortar to prepare a prescribed administration suspension, which was orally administered every day for 3 weeks after the date of the initial administration of the emulsion.

The experimental groups were a group of no treatment (intact group), a group administered with 0.5% of the CMC (hereinafter referred to as the control group) and a group administered with 300 mg/kg of Compd. No. 1245. The solution or the test compound was administered once a day. The number of animals in each group was 8.

2. Evaluation of Arthritis

The limb joint swelling of hindlimbs was evaluated by determining a change in the volume of the limb joints. The footpad volumes of the right and left hindlimbs of rats were measured total 7 times of the date of boosting, 2, 5, 7, 9, 12 and 14 days after the date of boosting by using a rat hindlimb footpad volume meter (TK-105, UNICON). The obtained results were expressed as an increasing rate after the date of boosting by taking the footpad volume on the date of boosting as 100%. The mean of the group was obtained as the mean of all the left and right hindlimb volumes in each group.

3. Results of evaluation

FIG. 5 illustrates results of arthritis when Compd. No. 1245 was orally administered every day for 3 weeks. Values in the figure are expressed as mean ±S.E. Student's t-tests or Wilcoxon tests were carried out comparing with the control group, and a P value of 0.05 or below was taken as significantly different. The group administered with Compd. No. 1245 significantly inhibited joint swelling (after 5, 7 and 14 days: P<0.01 and after 9 and 12 days: P<0.001) as compared with the control group at each time point of 5, 7, 9, 12 and 14 days after the boosting.

The results of Examples 2047 and 2048 show that the compounds of the present invention have effective remedial or prophylactic effects on diseases in association with chondrolysis of cartilage or osteolysis such as arthritis, rheumatoid arthritis, osteoarthritis, traumatic articular destruction, osteoporosis or tumor.

Example 2049 Studies on Inhibitors Actions in Masugi's Nephritis Model in WKY-Rats

1. Method (Common to Experiments 1 and 2)

Rabbits were immunized with a trypsin fraction of rat kidney cortex to provide an anti-glomerular basement membrane serum which was intravenously injected to 4-weeks-old female WKY rats (Charles River) in a dose of 2.5 mL/kg body weight to induce glomerulonephritis.

After injection of the antiserum, urine of each animal was collected for 24 hours with metabolic cages for rats (Clea Japan, Inc.) on the 1st, 4th, 7th, 10th and 14th days after the injection. The amount of the urine was measured by urine weight and the protein content in the urine was measured by using a kit for assaying proteins in urine and cerebrospinal fluid (Tonein TP-II, Otsuka Pharmaceutical Co., Ltd.) to determine the amount of proteins excreted in urine per day.

Serum of the animals subjected to the experiments was collected on the 15th day after injecting the antiserum, and creatinine concentration in blood was measured with a creatinine assay kit (Autosera®), Daiichi Pure Chemicals Co., Ltd.) using a Hitach±7070 model autoanalyzer.

The test compound was daily orally administered in a dose of 100 mg/kg body weight twice a day from the date of injecting the anti-glomerular basement membrane serum (about 10:00 a.m. and about 6:00 p.m. in Experiment 1 and about 10:00 a.m. and about 5:00 p.m. in Experiment 2). In the control group, only the solution (a 0.5% aqueous solution of sodium carboxymethylcellulose) was orally administered. The administration volume was 10 mL/kg body weight, and the number of animals (N) was 10.

2. Results and Discussion

The detection of proteinuria began in each experimental group on the 4th day after injecting the anti-glomerular basement membrane serum, and the concentration of the urinary proteins was subsequently increased to the 14th day with time to induce nephritis. In the group administered with Compd. No. 1583, a tendency to inhibit the concentration of urinary proteins by 26% was found as compared with the control group on the 7th day after injecting the antiserum. A significant inhibition of the concentration of urinary proteins was found by 51 and 54% on the 10th and 14th days (p<0.01, Mann-Whitney U test). (FIG. 6). When the creatinine concentration in blood was measured on the 15th day after injecting the anti-glomerular basement membrane serum, a significant decrease of 20% (p<0.01, Mann-Whitney U test) was found in the group administered with Compd. No. 1583 as compared with the control group (Table 53).

Therefore, it is found that the glomerular injury and renal function exacerbation of rats were alleviated with Compd. No. 1583 to inhibit nephritis.

TABLE 53 Inhibitory Effects on Serum Creatinine Serum Creatinine Concentration (mg/dl) on the 15th Day of Administering Compound Placebo Compd. No. 1583 0.49 ± 0.06 0.39 ± 0.03** 2-2. Experiment 2

The detection of proteinuria began in each experimental group on about the 4th day after injecting the anti-glomerular basement membrane serum, and the concentration of the urinary proteins was subsequently increased to the 14th day with time to confirm the induction of nephritis. In the group administered with Compd. No. 1245, a significant (p<0.001, Mann-Whitney U test) inhibition of the concentration of urinary proteins was respectively found by 74, 85, 81 and 82% on the 4th, 7th, 10th and 14th days after injecting the antiserum as compared with the control group (FIG. 7). When the creatinine concentration in blood was measured on the 15th day after injecting the anti-glomerular basement membrane serum, a significant decrease of 10% (p<0.05, Student's t-test) was found in the group administered with compound 1245 as compared with the control group (Table 54).

Therefore, it is found that the glomular injury and renal function exacerbation of rats were alleviated with Compd. No. 1245 to inhibit nephritis.

TABLE 54 Inhibitory Effects on Serum Creatinine Serum Creatinine Concentration (mg/dl) on the 15th Day of Administering Compd. No. 1245 Control Compd. No. 1245 0.53 ± 0.05 0.48 ± 0.04^(‡)

The above results show that the compound of the present invention has effective remedial or prophylactic effects on nephritis or nephropathy such as glomerulonephritis, interstitial nephritis or nephrotic syndrome.

Example 2050 Studies on Inhibitory Effects in Chronic Relapsing Experimental Allergic Encephalomyelitis in Mice

1. Method

Animal models of chronic recurrent experimental allergic encephalomyelitis were prepared according to the method described in the report by Okuda et al. [Okuda Y., et al. J. Neuroimmunol. 81, 201-210 (1998)]. Into the abdomen of 8-weeks-old female SJL/J×PL/J F1 mice (Jackson Lab.), were subcutaneously injected 100 μL of an emulsion of an Freund's incomplete adjuvant (Diffco) containing 500 μg of rabbit myelin basic protein (Sigma) and 500 μg of Mycobacterium tuberculosis H37Ra (Difco)/isotonic sodium chloride solution=1:1 (volume ratio). After 24 hours, 100 μL of isotonic sodium chloride solution containing 400 ng of Bordetella pertussis toxin (Sigma) was intraperitoneally injected to induce the chronic relapsing experimental allergic encephalomyelitis. The number of animals in each group was 10.

The test compound was suspended in a 0.5% (weight/volume) aqueous solution of sodium carboxymethylcellulose (Wako Pure Chemical Industries, Ltd.) with a mortar to prepare a prescribed suspension, which was orally administered from the date of injection of the emulsion.

Clinical symptoms of the chronic relapsing experimental allergic encephalomyelitis were evaluated by observation on animal individuals once a day by using the method described by Tahira et al. [“Methods of Immunological Experimental Procedures” p. 1178-1181, Nankodo (1995)]. Namely, score 0=normal; score 1=limp tail; score 2=slight walking abnormality; sore 3=apparent hindlimb paresis; score 4=complete hindlimb paralysis and score 5=moribund or death.

2. Results and Discussion

2-1. Experiment 1: Effects of Compd. No. 1583

Table 55 and FIG. 8 show the results to 41 days after injection of the emulsion.

The change in symptoms was expressed by means of the respective experimental groups on each observation day. In the maximal clinical scores in Table 55, the maximal value of the clinical scores shown in the observation period by the respective animals were adopted as the representative scores of the example. As to statistical analytical methods, nonparametric tests among some groups without comparison with to the control group were used for clinical scores and multiple comparisons with the control group (Dunnett's multiple comparison) were used for other evaluation items.

A tendency to delay the onset date (no significant difference), symptom inhibition (p<0.05) and shortening of onset period (p<0.05) were found at the first attack in the group administered with 100 mg/kg body weight of Compd. No. 1583 as compared with the control group. In the group administered with 30 mg/kg body weight of Compd. No. 1583, distinct effects on the items were not found; however, the tendency of dose-dependent effects was found. In FIG. 8, “compound 1” is not Compd. No. 1 in the present invention, but means the compound of Compd. No. 1583.

TABLE 55 Compd. No. 1583 Compd. No. 1583 Experimental Control 30 mg/kg 100 mg/kg Group Group body weight body weight First Attack Onset Date 12.6 ± 1.9  12.3 ± 1.9  13.6 ± 2.0  Maximal 3.9 ± 0.6 3.5 ± 0.9  2.4 ± 1.3* Clinical Score Duration of Clinical 8.8 ± 2.5 9.8 ± 3.3  5.7 ± 3.8* Sign Second Attack (Relapse) Onset Date 26.8 ± 7.5  26.3 ± 3.4  28.5 ± 4.7* Maximal 3.8 ± 0.8 3.7 ± 0.6  3.0 ± 0.9* Clinical Score Duration of Clinical Not Not calculated Not calculated Sign calculated Note: *p < 0.05 2-2. Experiment 2: Effects of Compd. No. 1245

Table 56 and FIG. 9 illustrate the results to 21 days after injection of the emulsion.

The change in symptoms was expressed as means of the respective experimental groups on each observation day. As to the maximal clinical scores in Table 56, the maximal values of clinical scores manifested by the respective animals during the observation period were adopted as representative scores of the example. As to statistical analytical methods, nonparametric tests between two groups without comparison with to the control group were used for clinical scores and two group comparison with the control group (Student's t-tests) was used for the other evaluation items.

The delay in onset date (p<0.05) and a tendency to inhibit symptoms (no significant difference) were found in the group administered with 300 mg/kg body weight of Compd. No. 1245 as compared with the control group.

TABLE 56 Compd. No. 1245 Experimental Group Control Group 300 mg/kg body weight Incidence (Number of 34/39 17/19 Onset Animals/Number of Immunized Animals) Onset Date 11.2 ± 2.0  13.2 ± 2.4* Maximal Clinical Score 3.0 ± 0.9 2.5 ± 1.5 Duration of Clinical Sign 5.5 ± 1.7 5.4 ± 2.4 *p < 0.05

The above results show that the compound of the present invention has effective remedial or prophylactic effects on demyelinating diseases such as multiple sclerosis.

The results shown in Examples 2043 to 2050 reveal that the compound of the present invention as a chemokine receptor antagonist can be useful as remedies or prophylactics for various diseases considered to be associated with chemokines such as MIP-1 α and/or MCP-1 such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, pulmonary fibrosis, cardiomyopathy, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, sepsis, allergic rhinitis and allergic dermatitis.

Example 2051 Production of Tablets

A tablet containing 30 mg of Compd. No. 1583 was prepared according to the following prescription:

Compd. No. 1583 30 mg Lactose 87 mg Starch 30 mg Magnesium stearate  3 mg

Example 2052 Production of Parenteral Injection

Solutions for injection containing 0.3 mg of hydrochloride of Compd. No. 1583 in 1 mL were prepared according to the following prescription:

Compd. No. 1583 (hydrochloride) 30 mg Sodium chloride 900 mg Distilled water for injection 100 mL

INDUSTRIAL APPLICABILITY

Cyclic amine compounds used in the present invention, pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C₁-C₆ alkyl addition salts thereof as a chemokine receptor antagonist have inhibitory activities on actions of chemokines such as MIP-1 α and/or MCP-1 on target cells. Therefore, the cyclic amine compounds, pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C₁-C₆ alkyl addition salts thereof are useful as remedies and/or prophylactics for diseases such as atherosclerosis, rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis (nephropathy), multiple sclerosis, pulmonary fibrosis, cardiomyopathy, hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis, congestive heart failure, viral meningitis, cerebral infarction, neuropathy, Kawasaki disease, sepsis, allergic rhinitis and allergic dermatitis wherein infiltration of leukocytes such as monocytes or lymphocytes into tissues plays a principal role in progression and maintenance of diseases. 

1. A method for treatment of (nephropathy) or multiple sclerosis comprising administering to a subject an effective amount of at least one compound represented by the following formula (I), pharmaceutically acceptable acid addition salts thereof or pharmaceutically acceptable C₁-C₆ alkyl addition salts thereof as an active ingredient,

wherein R¹ is a phenyl group, or an indolyl group; the phenyl group or the indolyl group in the above R¹ is optionally substituted with an optional number of halogen atoms or C₁-C₆ alkyl groups; R² is a hydrogen atom; j is 0; k is 1 or 2; m is 2; n is 0 or 1; R³ is a hydrogen atom; R⁴ is a hydrogen atom; R⁵ is a hydrogen atom; p is 0; q is 0; G is a group represented by —NH—CO—; R⁶ is a phenyl group; the phenyl group, in the above R⁶ is optionally substituted with an optional number of halogen atoms, C₁-C₆ alkyl groups, C₁-C₆ alkoxyl groups, or amino groups; wherein the C₁-C₆ alkyl groups or the C₁-C₆ alkoxyl groups may further be substituted with 1 to 3 halogen atoms.
 2. The method according to claim 1, wherein the method is for treatment of nephropathy.
 3. The method according to claim 1, wherein the method is for treatment of multiple sclerosis.
 4. The method according to claim 1, wherein the nephropathy is nephritis. 